5ht2c receptor modulator compositions and methods of use

ABSTRACT

The present invention relates to a composition comprising phentermine and a selective 5HT-2C receptor agonist. In addition, the invention relates to a composition comprising phentermine and a selective 5HT-2C receptor agonist having Formula (I): or a pharmaceutically acceptable salt, solvate or hydrate thereof. These compositions are useful in pharmaceutical compositions whose use includes the treatment of obesity.

CROSS-REFERENCE TO RELATED APPLICATIONS

This is a continuation of U.S. application Ser. No. 13/418,151 filedMar. 12, 2012, which is a divisional of U.S. patent application Ser. No.11/793,941 filed Apr. 11, 2008 entitled “5HT2C Receptor ModulatorCompositions And Methods Of Use,” now U.S. Pat. No. 8,153,621 issuedApr. 10, 2012, which is a 35 USC 371 National Stage Entry ofPCT/US2005/046654 filed Dec. 21, 2005, which claims the benefit of U.S.Provisional Application No. 60/688,901 filed Jun. 8, 2005, and U.S.Provisional Application No. 60/638,667 filed Dec. 23, 2004, each ofwhich is incorporated herein by reference in its entirety.

FIELD OF THE INVENTION

The present invention relates to compounds which act as modulators of5HT_(2C) receptors, compositions including the compounds, and methods ofusing the compounds and compositions.

BACKGROUND OF THE INVENTION

Obesity is a life-threatening disorder in which there is an increasedrisk of morbidity and mortality arising from concomitant diseases suchas type II diabetes, hypertension, stroke, cancer and gallbladderdisease.

Obesity is now a major healthcare issue in the Western World andincreasingly in some third world countries. The increase in numbers ofobese people is due largely to the increasing preference for high fatcontent foods but also the decrease in activity in most people's lives.In the last 10 years there has been a 30% increase in the incidence ofobesity in the USA such that currently about 30% of the population ofthe USA is now considered obese.

Whether someone is classified as overweight or obese is generallydetermined on the basis of their body mass index (BMI) which iscalculated by dividing body weight (kg) by height squared (m²). Thus,the units of BMI are kg/m² and it is possible to calculate the BMI rangeassociated with minimum mortality in each decade of life. Overweight isdefined as a BMI in the range 25-30 kg/m² and obesity as a BMI greaterthan 30 kg/m₂ (see Table 1 below).

TABLE 1 CLASSIFICATION OF WEIGHT BY BODY MASS INDEX (BMI) BMICLASSIFICATION <18.5 Underweight 18.5-24.9 Normal 25.0-29.9 Overweight30.0-34.9 Obesity (Class I) 35.0-39.9 Obesity (Class II) >40   ExtremeObesity (Class III)

As the BMI increases there is an increased risk of death from a varietyof causes that are independent of other risk factors. The most commondiseases associated with obesity are cardiovascular disease(particularly hypertension), diabetes (obesity aggravates thedevelopment of diabetes), gall bladder disease (particularly cancer) anddiseases of reproduction. Research has shown that even a modestreduction in body weight can correspond to a significant reduction inthe risk of developing coronary heart disease.

There are problems however with the BMI definition in that it does nottake into account the proportion of body mass that is muscle in relationto fat (adipose tissue). To account for this, obesity can also bedefined on the basis of body fat content: greater than 25% in males andgreater than 30% in females.

Obesity considerably increases the risk of developing cardiovasculardiseases as well. Coronary insufficiency, atheromatous disease, andcardiac insufficiency are at the forefront of the cardiovascularcomplications induced by obesity. It is estimated that if the entirepopulation had an ideal weight, the risk of coronary insufficiency woulddecrease by 25% and the risk of cardiac insufficiency and of cerebralvascular accidents would decrease by 35%. The incidence of coronarydiseases is doubled in subjects less than 50 years of age who are 30%overweight. The diabetes patient faces a 30% reduced lifespan. After age45, people with diabetes are about three times more likely than peoplewithout diabetes to have significant heart disease and up to five timesmore likely to have a stroke. These findings emphasize theinter-relations between risks factors for diabetes and coronary heartdisease and the potential value of an integrated approach to theprevention of these conditions based on the prevention of obesity(Perry, I. J., et al., BMJ 310, 560-564 (1995)).

Diabetes has also been implicated in the development of kidney disease,eye diseases and nervous system problems. Kidney disease, also callednephropathy, occurs when the kidney's “filter mechanism” is damaged andprotein leaks into urine in excessive amounts and eventually the kidneyfails. Diabetes is also a leading cause of damage to the retina at theback of the eye and increases risk of cataracts and glaucoma. Finally,diabetes is associated with nerve damage, especially in the legs andfeet, which interferes with the ability to sense pain and contributes toserious infections. Taken together, diabetes complications are one ofthe nation's leading causes of death.

The first line of treatment is to offer diet and life style advice topatients such as reducing the fat content of their diet and increasingtheir physical activity. However, many patients find this difficult andneed additional help from drug therapy to maintain results from theseefforts.

Most currently marketed products have been unsuccessful as treatmentsfor obesity because of a lack of efficacy or unacceptable side-effectprofiles. The most successful drug so far was the indirectly acting5-hydroxytryptamine (5-HT) agonist d-fenfluramine (Redux™) but reportsof cardiac valve defects in up to one third of patients led to itswithdrawal by the FDA in 1998.

In addition, two drugs have recently been launched in the USA andEurope: Orlistat (Xenical™), a drug that prevents absorption of fat bythe inhibition of pancreatic lipase, and Sibutramine (Reductil™), a5-HT/noradrenaline re-uptake inhibitor. However, side effects associatedwith these products may limit their long-term utility. Treatment withXenical™ is reported to induce gastrointestinal distress in somepatients, while Sibutramine has been associated with raised bloodpressure in some patients.

Serotonin (5-HT) neurotransmission plays an important role in numerousphysiological processes both in physical and in psychiatric disorders.5-HT has been Implicated in the regulation of feeding behavior. 5-HTappears to work by inducing a feeling of fullness or satiety so eatingstops earlier and fewer calories are consumed. It has been shown that astimulatory action of 5-HT on the 5HT_(2C) receptor plays an importantrole in the control of eating and in the anti-obesity effect ofd-fenfluramine. As the 5-HT_(2C) receptor is expressed in high densityin the brain (notably in the limbic structures, extrapyramidal pathways,thalamus and hypothalamus, i.e. PVN and DMH, and predominantly in thechoroid plexus) and is expressed in low density or is absent inperipheral tissues, a selective 5-HT_(2C) receptor agonist can be a moreeffective and safe anti-obesity agent. Also, 5-HT_(2C) knockout mice areoverweight with cognitive impairment and susceptibility to seizure.

It is believed that 5HT_(2C) may play a role in obsessive compulsivedisorder, some forms of depression, and epilepsy. Accordingly, agonistscan have anti-panic properties, and properties useful for the treatmentof sexual dysfunction.

In sum, the 5HT_(2C) receptor is a receptor target for the treatment ofobesity and psychiatric disorders, and it can be seen that there is aneed for selective 5HT_(2C) agonists which safely decrease food intakeand body weight. The present invention is directed to these, as well asother, important ends.

SUMMARY OF THE INVENTION

In a first aspect, the invention features a composition comprisingphentermine and a selective 5HT-2C receptor agonist.

In a second aspect, the invention features a composition according tothe first aspect where the selective 5HT-2C receptor agonist has Formula(I):

or a pharmaceutically acceptable salt, solvate or hydrate thereof

wherein:

-   -   R₁ is H or C₁₋₈ alkyl;    -   R₂ is C₁₋₈ alkyl, —CH₂—O—C₁₋₈ alkyl, —C(═O)—O—C₁₋₈ alkyl,        —C(═O)—NH—C₁₋₈ alkyl, OH, or CH₂OH;    -   R_(2a) is H;    -   or R₂ and R_(2a) together form —CH₂—CH₂—;    -   R₃ and R₄ are each independently H, halogen, perhaloalkyl, CN,        OR₅, SR₅, NHR₅, N(R₅)₂, OH, aryl, or heteroaryl, wherein said        aryl can be optionally substituted with up to two substituents        selected from C₁₋₈ alkyl, halogen, perhalo alkyl, and alkoxy,        and said heteroaryl can be optionally substituted with up to two        substituents selected from halogen and C₁₋₈ alkyl;    -   or R₃ and R₄ together with the atoms to which they are attached        can form a 5- or 6-member heterocyclic ring having one O atom;    -   each R5 is independently C₁₋₈ alkyl, C₁₋₈ alkenyl, aryl,        heteroaryl, arylalkyl, heteroarylalkyl or perhaloalkyl, or        allyl; and    -   R₆ is H or C₁₋₈ alkyl.

In a third aspect, the invention features a composition according to thesecond aspect wherein:

-   -   R₃ is halogen, perhaloalkyl, CN, SR₅, NHR₅, N(R₅)₂, aryl, or        heteroaryl, wherein said aryl can be optionally substituted with        up to two substituents selected from C₁₋₈ alkyl, halogen,        perhalo alkyl, and alkoxy, and said heteroaryl can be optionally        substituted with up to two substituents selected from halogen        and C₁₋₈ alkyl; and    -   R₄ is H, halogen, perhaloalkyl, CN, SR₅, NHR₅, N(R₅)₂, aryl, or        heteroaryl, wherein said aryl can be optionally substituted with        up to two substituents selected from C₁₋₈ alkyl, halogen,        perhalo alkyl, and alkoxy, and said heteroaryl can be optionally        substituted with up to two substituents selected from halogen        and C₁₋₈ alkyl;    -   wherein heteroaryl is pyrrolyl, pyrazolyl, imldazolyl,        triazolyl, tetrazolyl, pyridyl, pyrimidinyl, furanyl, pyranyl,        thienyl, benzimidazolyl, quinolinyl, isoquinolinyl, oxazolyl,        thiazolyl or thiadiazolyl.

In a fourth aspect, the invention features a composition according tothe second or third aspect wherein R₁ is H. In addition, the fourthaspect features a composition according to the second or third aspectwherein R₁ is methyl.

In a fifth aspect, the invention features a composition according to thesecond, third, or fourth aspect wherein R₂ is methyl, ethyl, n-propyl orisopropyl. In addition, the fifth aspect features a compositionaccording to the second, third, or fourth aspect wherein R₂ is methyl orethyl. Further, the fifth aspect features a composition according to thesecond, third, or fourth aspect wherein R₂ and R_(2a) together form—CH₂CH₂—.

In a sixth aspect, the invention features a composition according to thesecond through fifth aspect wherein R₃ is chlorine. In addition, thesixth aspect features a composition according to the second throughfifth aspect wherein R₃ is bromine. Further, the sixth aspect features acomposition according to the second through fifth aspect wherein R₃ isperhaloalkyl. Also, the sixth aspect features a composition according tothe second through fifth aspect wherein R₃ is CF₃. Further, the sixthaspect features a composition according to the second through fifthaspect wherein R₃ is selected from the group consisting of thienyl,furanyl, pyrrolyl, pyrazolyl and imidazolyl.

In a seventh aspect, the invention features a composition according tothe second through sixth aspect wherein R₄ is selected from the groupconsisting of thienyl, furanyl, pyrrolyl, pyrazolyl and imidazolyloptionally substituted with one or two substituents selected fromhalogen or methyl. In addition, the seventh aspect features acomposition according to the second through sixth aspect wherein R₄ isphenyl optionally substituted with up to two substituents selected fromC₁₋₈ alkyl, halogen, and alkoxy.

In an eighth aspect, the invention features a composition according tothe second aspect wherein:

-   -   R₂ is methyl, ethyl, isopropyl, or CH₂OH; or R₂ and R_(2a) taken        together form —CH₂CH₂—;    -   R₃ is halogen, or a 5-membered heteroaryl ring having up to two        heteroatoms selected from O, N and S, and up to two substituents        selected from halogen and C₁₋₈ alkyl;    -   R₄ is H, a 5-membered heteroaryl ring having up to two        heteroatoms selected from O, N and S and up to two substituents        selected from halogen and C₁₋₈ alkyl, or phenyl optionally        substituted with up to two substituents selected from C₁₋₈        alkyl, halogen, and alkoxy;    -   R₆ is H or methyl; or a pharmaceutically acceptable salt,        solvate or hydrate thereof.

In addition, the eighth aspect features a composition of the secondaspect wherein:

-   -   R₁ is H;    -   R₂ is methyl;    -   R₃ is chlorine, bromine, or thienyl;    -   R is pyrazolyl-3-yl or phenyl wherein said pyrazolyl-3-yl        optionally has up to two substituents selected from halogen and        C₁₋₈ alkyl, and said phenyl optionally has a single halogen        substitutent; and    -   R₆ is H; or a pharmaceutically acceptable salt, solvate or        hydrate thereof.

Further, the eighth aspect features a composition of the second aspectwherein:

-   -   R₁ is H or Me;    -   R₂ is Me, Et, or OH;    -   R_(2a) is H;    -   R₃ is F, Cl, Br, I, CF₃, or 2-chlorophenyl;    -   R₄ is H; and    -   R₆ is H.

In addition, the eighth aspect features a composition of the secondaspect wherein:

-   -   R₁ is H;    -   R₂ is C₁₋₈ alkyl;    -   R_(2a) is H;    -   R₃ is halogen;    -   R₄ is H; and    -   R₆ is H.

In a ninth aspect, the invention features a composition according to thefirst or second aspect wherein said selective 5HT-2C receptor agonist isselected from the group consisting of:

-   8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine;-   8-bromo-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine;-   8-iodo-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine;-   8-trifluoromethyl-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine;-   8-trifluoromethyl-1-ethyl-2,3,4,5-tetrahydro-1H-3-benzazepine;-   8-chloro-1-ethyl-2,3,4,5-tetrahydro-1H-3-benzazepine;-   8-bromo-1-ethyl-2,3,4,5-tetrahydro-1H-3-benzazepine;-   8-iodo-1-ethyl-2,3,4,5-tetrahydro-1H-3-benzazepine;-   7,8-dichloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine;-   7,8-dichloro-1-ethyl-2,3,4,5-tetrahydro-1H-3-benzazepine;-   8-chloro-7-fluoro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine;-   8-chloro-7-methoxy-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine; and-   8-chloro-7-fluoro-1-ethyl-2,3,4,5-tetrahydro-1H-3-benzazepine;    -   or a pharmaceutically acceptable salt, solvate or hydrate        thereof.

In addition, the ninth aspect features a composition according to thefirst or second aspect wherein said selective 5HT-2C receptor agonist is(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof.

In a tenth aspect, the invention features a composition according to thefirst through ninth aspect further comprising a pharmaceuticallyacceptable carrier.

In an eleventh aspect, the invention features a method of decreasingfood intake of a mammal comprising administering to said mammal apharmaceutically effective amount of a combination comprising an amountof (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine and anamount of phentermine, wherein said(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine andphentermine are provided in amounts to give a synergistic effect indecreasing food intake in said mammal. In one embodiment, the amount of(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine alone and theamount of phentermine alone are therapeutically sub-effective indecreasing food intake in said mammal.

In a twelfth aspect, the invention features a method of inducing satietyin a mammal comprising administering to said mammal a pharmaceuticallyeffective amount of a combination comprising an amount of(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine and an amountof phentermine, wherein said(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine andphentermine are provided in amounts to give a synergistic effect ininducing satiety in said mammal. In one embodiment, the amount of(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine alone and theamount of phentermine alone are therapeutically sub-effective ininducing satiety in said mammal.

In a thirteenth aspect, the invention features a method of controllingweight gain of a mammal comprising administering to said mammal apharmaceutically effective amount of a combination comprising an amountof (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine and anamount of phentermine, wherein said(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine andphentermine are provided in amounts to give a synergistic effect incontrolling weight gain in said mammal. In one embodiment, the amount of(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine alone and theamount of phentermine alone are therapeutically sub-effective incontrolling weight gain in said mammal.

In a fourteenth aspect, the invention features a method of prophylaxisor treatment of obesity comprising administering to a patient in need ofsuch prophylaxis or treatment a pharmaceutically effective amount of acombination comprising an amount of(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine and an amountof phentermine, wherein said(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine andphentermine are provided in amounts to give a synergistic effect indecreasing food intake in said mammal. In one embodiment, the amount of(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine alone and theamount of phentermine alone are therapeutically sub-effective indecreasing food intake in said mammal.

In some embodiments, some of the foregoing methods of the inventionfurther comprising the step of identifying a subject, said subject beingin need of decreasing food intake, controlling weight gain, or treatingobesity, wherein said identifying step is performed prior toadministering to said subject said pharmaceutically effective amount ofsaid compound or composition of the invention.

Applicants reserve the right to exclude any one or more of the compoundsfrom any of the embodiments of the invention. Applicant additionallyreserves the right to exclude any disorder from any of the embodimentsof the invention.

BRIEF DESCRIPTION OF THE FIGURES

FIGS. 1A-1G illustrate the effects of seven different 5HT-2C receptoragonist compounds described in the invention on food intake infood-deprived rats.

FIG. 2 shows the supra additive (synergistic) effect of phentermine andthe selective 5HT-2C receptor agonist8-Chloro-7-methoxy-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine (Cmpd A)on feeding in rats.

FIGS. 3A and 3B show the supra additive (synergistic) effect ofphentermine and the selective 5HT-2C receptor agonist(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine (Cmpd B) onfood intake in female (FIG. 3A) and male (FIG. 3B) rats.

FIGS. 4A and 4B show the supra additive (synergistic) effect ofphentermine and the selective 5HT-2C receptor agonist(R)-1-(5-Chloro-2-fluoro-phenyl)-2-methyl-piperazine (Cmpd C) on foodintake in female (FIG. 4A) and male (FIG. 4B) rats.

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to the combination of 5HT-2C receptoragonist compounds with other agents in order to decrease certain 5HT-2Creceptor related behaviors such as feeding. While the 5HT-2C receptoragonist compounds described in the invention can be employed as the soleactive agent in a pharmaceutical (i.e., mono-therapy), they canadvantageously be used in combination with other active ingredients(i.e., combination-therapy) which can facilitate the therapeutic effectof the compound. Therefore, one aspect of the present invention includesmethods of prophylaxis and/or treatment of a 5HT-2C receptor relatedcondition such as obesity, or a condition related thereto, comprisingadministering to an individual in need of said prophylaxis and/ortreatment a combination comprising an amount of a selective 5HT-2Creceptor agonist in combination with an amount of one or more additionalpharmaceutical agent as described herein. In one embodiment, the amountof the selective 5HT-2C receptor agonist and the amount of the one ormore additional pharmaceutical agents alone are therapeuticallysub-effective in the prophylaxis and/or treatment of the condition butwhen combined these compounds act synergistically to prevent or treatthe condition.

Suitable pharmaceutical agents that can be used in combination with theselective 5HT-2C receptor agonists include, for example, anti-obesityagents such as apolipoprotein-B secretion/microsomal triglyceridetransfer protein (apo-B/MTP) inhibitors, MCR-4 agonists,cholescystokinin-A (CCK-A) agonists, serotonin and norepinephrinereuptake inhibitors (for example, sibutramine), sympathomimetic agensts,β₃ adrenergic receptor agonists, dopamine agonists (for example,bromocriptine), melanocyte-stimulating hormone receptor analogs,cannabinoid 1 receptor antagonists [for example, SR141716:N-(piperidin-1-yl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide],melanin concentrating hormone antagonists, leptins (the OB protein),leptin analogues, leptin receptor agonists, galanin antagonists, lipaseinhibitors (such as tetrahydrolipstatin, i.e., Orlistat), anorecticagents (such as a bombesin agonist), Neuropeptide-Y antagonists,thyromimetic agents, dehydroepiandrosterone or an analogue thereof,glucocorticoid receptor agonists or antagonists, orexin receptorantagonists, urocortin binding protein antagonists, glucagon-likepeptide-1 receptor agonists, ciliary neutrotrophic factors (such asAxokine™ available from Regeneron Pharmaceuticals, Inc., Tarrytown, N.Y.and Procter & Gamble Company, Cincinnati, Ohio), human agouti-relatedproteins (AGRP), ghrelin receptor antagonists, histamine 3 receptorantagonists or reverse agonists, neuromedin U receptor agonists,noradrenergic anorectic agents (for example, phentermine, mazindol andthe like) and appetite suppressants (for example, bupropion).

Other anti-obesity agents, including the agents set forth infra, arewell known, or will be readily apparent in light of the instantdisclosure, to one of ordinary skill in the art.

In some embodiments, the anti-obesity agents are selected from the groupconsisting of phentermine, orlistat, sibutramine, bromocriptine,ephedrine, leptin, and pseudoephedrine. In one embodiment, theanti-obesity agent is phentermine. In a further embodiment, compositionsof the present invention and combination therapies are administered inconjunction with exercise and/or a sensible diet.

It will be understood that the scope of combination therapy of thecompounds of the present invention with other anti-obesity agents,anorectic agents, appetite suppressant and related agents is not limitedto those listed above, but includes in principle any combination withany pharmaceutical agent or pharmaceutical composition useful for thetreatment of overweight and obese individuals.

Other suitable pharmaceutical agents, in addition to anti-obesityagents, that can be used in combination with the compounds of thepresent invention include agents useful in the treatment of concomitantdiseases. For example, individuals who are overweight or obese increasetheir risk of morbidity and mortality arising from concomitant diseases,such as, but not limited to, congestive heart failure, type II diabetes,atherosclerosis, dyslipidemia, hyperinsulinemia, hypertension, insulinresistance, hyperglycemia, retinopathy, nephropathy and neuropathy.Treatment for one or more of the diseases cited herein include the useof one or more pharmaceutical agents known in the art belonging to theclasses of drugs referred to, but not limited to, the following:sulfonylureas, meglitinides, biguanides, aglucosidase inhibitors,peroxisome proliferators-activated receptor-γ (i.e., PPAR-γ) agonists,insulin, insulin analogues, HMG-CoA reductase inhibitors,cholesterol-lowering drugs (for example, fibrates that include:fenofibrate, bezafibrate, gemfibrozil, clofibrate and the like; bileacid sequestrants which include: cholestyramine, colestipol and thelike; statins, and niacin), antiplatelet agents (for example, aspirinand adenosine diphosphate receptor antagonists that include:clopidogrel, ticlopidine and the like), angiotensin-converting enzymeinhibitors, angiotensin II receptor antagonists and adiponectin.

It will be understood that the scope of combination therapy of thecompounds of the present invention with other pharmaceutical agents isnot limited to those listed herein, supra or infra, but includes inprinciple any combination with any pharmaceutical agent orpharmaceutical composition useful for the treatment diseases, conditionsor disorders that are linked to overweight and obese individuals.

Combination therapies have been used in the treatment of diseases;however, care must be taken when combining drugs since certain drugs caninteract in a harmful manner. The combination of two agents that treatthe same condition is generally expected to result in an additive effectmeaning that the degree of the effect is the sum of the effect of eachdrug alone. Applicants disclose herein that the combination of aselective 5HT-2C agonist and another drug such as phentermine can resultin a supra additive or synergistic effect on food intake (see FIGS. 2,3A and B, 4A and B). A synergistic effect means that the decrease infood intake observed with the combination therapy is greater than thatseen by adding the decrease in food intake of each compound together.One advantage of using a synergistic combination therapy is that less ofeach compound is required to achieve a significant decrease in foodintake and so fewer side effects can result from treatment. In somecases, side effects are not seen at the lower doses used. Also, in somecases, the side effect profile of one drug can mitigate or average outthe side effect profile of the other drug. For example, one of the drugsmay result in increased blood pressure and the other drug results inlowered blood pressure so that the combination therapy does not effectblood pressure. Another potential advantage of combination therapy isthat, since less compound is required, the cost of therapy can bereduced.

This application incorporates by reference, in their entirety, U.S.Provisional Application No. 60/372,058, filed Apr. 12, 2002; U.S.Provisional Patent Application No. 60/405,495, filed Aug. 23, 2002; U.S.Provisional Patent Application No. 60/434,607, filed Dec. 18, 2002;U.S.NonProvisional patent application Ser. No. 10/410,991, filed Apr.10, 2003 and U.S. NonProvisional patent application Ser. No. 10/917,979,filed Aug. 13, 2004. This application claims priority to, andincorporates by reference in their entirety, U.S. Non-Provisionalapplication Ser. No. 13/418,151 filed Mar. 12, 2012, U.S.Non-Provisional application Ser. No. 11/793,941 filed Apr. 11, 2008, nowU.S. Pat. No. 8,153,621 issued Apr. 10, 2012, U.S. ProvisionalApplication No. 60/638,667, filed Dec. 23, 2004, and U.S. ProvisionalApplication No. 60/688,901, filed Jun. 8, 2005.

In one aspect, the invention provides a composition comprisingphentermine and a selective 5HT-2C receptor agonist.

Phentermine (1,1-Dimethyl-2-phenyl-ethylamine) includes phenterminederivatives or pharmaceutically acceptable salts thereof, such as, butnot limited to, chlorphentermine(2-(4-Chloro-phenyl)-1,1-dimethyl-ethylamine) and the like. In oneembodiment, phentermine is in the HCl salt form.

As used herein, the term “agonist” is intended to mean moieties thatactivate the intracellular response when they bind to the receptor, orenhance GTP binding to membranes. In the context of the presentinvention, a pharmaceutical composition comprising a 5HT_(2C) receptoragonist of the invention can be utilized for modulating the activity ofthe 5HT_(2C) receptor, decreasing food intake, inducing satiation (i.e.,the feeling of fullness), controlling weight gain, treating obesity,decreasing body weight and/or affecting metabolism such that therecipient loses weight and/or maintains weight. Such pharmaceuticalcompositions can be used in the context of disorders and/or diseaseswhere weight gain is a component of the disease and/or disorder such as,for example, obesity.

The term “antagonist” is intended to mean moieties that competitivelybind to the receptor at the same site as agonists (for example, theendogenous ligand), but which do not activate the intracellular responseinitiated by the active form of the receptor, and can thereby inhibitthe intracellular responses by agonists or partial agonists. Antagonistsdo not diminish the baseline intracellular response in the absence of anagonist or partial agonist.

As used herein the term “selective 5HT-2C receptor agonist” means anagonist compound that is selective for 5HT-2C receptor compared to otherreceptors that decrease food intake. For example, a selective 5HT-2Creceptor agonist has a significantly higher binding affinity for the5HT-2C receptor than for another receptor that can decrease food intakesuch as the 5HT-1b receptor. Therefore, for example, a selective 5HT-2Creceptor agonist can have 10-fold, 20-fold, 30-fold, 40-fold, 50-fold,60-fold, 70-fold, 80-fold, 90-fold, 100-fold, or 150-fold or more higherbinding affinity for the 5HT-2C receptor than for another receptor suchas the 5HT-1b receptor. As understood by one skilled in the art,selectivity can be determined, for example, using a receptor bindingassay or a functional assay. One way to assess selectivity is to performa feeding assay as disclosed herein (see Example 2) with a potentialselective 5HT-2C receptor agonist and then challenge the animals with aselective 5HT-2C antagonist, for example. SB 242084 (Sigma). If the foodintake effect is abolished (or very significantly decreased) then theeffect is deemed to be occurring through the 5HT-2C receptor and notthrough a different receptor.

The term “selective 5HT-2C receptor agonist” does not include compoundssuch as dexfenfluramine which are 5HT-releasing agents or compounds suchas fluoxetine which are 5HT uptake inhibitors. In addition, the term“selective 5HT-2C receptor agonist” does not include non-selective 5HTagonists such as m-chlorophenylpiperazine (mCPP) orm-trifluoromethylphenylpiperazine (TFMPP) which have significant effectsat the 5HT-1b receptor. For example, TFMPP causes decreased food intake;however, the decrease in food intake is not abolished when a selective5HT-2C antagonist such as SB 242084 is added.

As disclosed herein, compositions of the invention can comprisephentermine and a selective 5HT-2C receptor agonist. The phentermine andselective 5HT-2C receptor agonist can be delivered as separate entitiesor the phentermine and selective 5HT-2C receptor agonist can be combinedto form one entity. For example, phentermine and selective 5HT-2Creceptor agonist can be delivered as two separate pills or capsules orthey can be combined to form one pill or capsule.

The invention also provides a composition comprising phentermine and aselective 5HT-2C receptor agonist where the selective 5HT-2C receptoragonist has Formula (I):

or a pharmaceutically acceptable salt, solvate or hydrate thereof

wherein:

-   -   R₁ is H or C₁₋₈ alkyl:    -   R₂ is C₁₋₈ alkyl, —CH₂—O—C₁₋₈ alkyl, —C(═O)—O—C₁₋₈ alkyl.        —C(═O)—NH—C₁₋₈ alkyl, OH, or CH₂OH;    -   R_(2a) is H:    -   or R₂ and R_(2a) together form —CH₂CH₂—;    -   R₃ and R₄ are each independently H, halogen, perhaloalkyl, CN,        OR₅, SR₅, NHR₅, N(R₅)₂, OH, aryl, or heteroaryl, wherein said        aryl can be optionally substituted with up to two substituents        selected from C₁₋₈ alkyl, halogen, perhalo alkyl, and alkoxy,        and said heteroaryl can be optionally substituted with up to two        substituents selected from halogen and C₁₋₈ alkyl;    -   or R₃ and R₄ together with the atoms to which they are attached        can form a 5- or 6-member heterocyclic ring having one O atom;    -   each R₅ is independently C₁₋₈ alkyl, C₁₋₈ alkenyl, aryl,        heteroaryl, arylalkyl, heteroarylalkyl or perhaloalkyl, or        allyl; and    -   R₆ is H or C₁₋₈ alkyl.

Some embodiments of the present invention pertain to a compositioncomprising phentermine and a selective 5HT-2C receptor agonist where theselective 5HT-2C receptor agonist has Formula (I):

or a pharmaceutically acceptable salt, solvate or hydrate thereof

wherein:

-   -   R₁ is H or C₁₋₈ alkyl;    -   R₂ is C₁₋₈ alkyl, —CH₂—O—C₁₋₈ alkyl, —C(═O)—O—C₁₋₈ alkyl,        —C(═O)—NH—C₁₋₈ alkyl, OH, or CH₂OH;    -   R_(2a) is H;        -   or R₂ and R_(2a) together form —CH₂—CH₂—;    -   R₃ is halogen, perhaloalkyl, CN, SR₅, NHR₅, N(R₅)₂, aryl, or        heteroaryl, wherein said aryl can be optionally substituted with        up to two substituents selected from C₁₋₈ alkyl, halogen,        perhalo alkyl, and alkoxy, and said heteroaryl can be optionally        substituted with up to two substituents selected from halogen        and C₁₋₈ alkyl;    -   R₄ is H, halogen, perhaloalkyl, CN, SR₅, NHR₅, N(R₅)₂, aryl, or        heteroaryl, wherein said aryl can be optionally substituted with        up to two substituents selected from C₁₋₈ alkyl, halogen,        perhalo alkyl, and alkoxy, and said heteroaryl can be optionally        substituted with up to two substituents selected from halogen        and C₁₋₈ alkyl;    -   each R₆ is independently C₁₋₈ alkyl, C₁₋₈ alkenyl, aryl,        heteroaryl, arylalkyl, heteroarylalkyl or perhaloalkyl, or        allyl; and    -   R₆ is H or C₁₋₈ alkyl;    -   wherein heteroaryl is pyrrolyl, pyrazolyl, imidazolyl,        triazolyl, tetrazolyl, pyridyl, pyrimidinyl, furanyl, pyranyl,        thienyl, benzimidazolyl, quinolinyl, Isoquinolinyl, oxazolyl,        thiazolyl or thiadiazolyl;    -   or a pharmaceutically acceptable salt, solvate or hydrate        thereof provided that:    -   (i) if R₆ is other than H, then neither R₃ nor R₄ can be H;    -   (ii) if R₁ and R₂ are methyl, and R₄ is H, then R₃ cannot be        NHR₅ or N(R₅)₂; and    -   (iii) if R₁ and R₂ are methyl, and R₄ is H, then R₃ cannot be        imidazole, substituted imidazole, or an imidazole derivative.

Some embodiments of the present invention pertain to a compositioncomprising phentermine and a selective 5HT-2C receptor agonist where theselective 5HT-2C receptor agonist has Formula (I):

wherein:

-   -   R₁ is: —H or C₁₋₈alkyl;    -   R₂ is: C₁₋₈alkyl, —CH₂—O—C₁₋₈alkyl, —C(═O)—O—C₁₋₈alkyl,        —C(═O)—NH—C₁₋₈alkyl, —OH, or —CH₂OH;    -   R_(2a), is: —H;    -   or R₂ and R_(2a) together form —CH₂—CH₂—;    -   R₃ is: halogen; perhaloalkyl; or a 5-membered heteroaryl ring        having up to two heteroatoms selected from O, N and S;    -   R₄ is —H, halogen, pemaloalkyl, —CN, —OR₅, —SR₅, —NHR₅, —N(R₅)₂,        —OH, aryl, or heteroaryl, wherein said aryl can be optionally        substituted with up to two substituents selected from C₁₋₈alkyl,        halogen, perhaloalkyl, and alkoxy, and said heteroaryl can be        optionally substituted with up to two substituents selected from        halogen and C₁₋₈alkyl;    -   or:    -   R₃ and R₄ together with the atoms to which they are attached        form a 5- or 6-member heterocyclic ring having one O atom;    -   each R₅ is independently C₁₋₈alkyl, C₁₋₈alkenyl, aryl,        heteroaryl, arylalkyl, heteroarylalkyl or perhaloalkyl, or        allyl; and    -   R₆ is —H or C₁₋₈alkyl;    -   or a pharmaceutically acceptable salt, solvate or hydrate        thereof:    -   provided that:    -   if R₆ is other than —H, then R₄ cannot be —H; and    -   if R₁ and R₂ are methyl, and R₄ is —H, then R₃ cannot be        imidazole, substituted imidazole, or an imidazole derivative;    -   and wherein:    -   aryl denotes a monocyclic or polycyclic aromatic group having        from 3 to 14 carbon atoms;    -   heteroaryl denotes a monocyclic or polycyclic aromatic group        having from 3 to 14 carbon atoms, and from 1 to 4 ring        heteroatoms selected from O, N, and S;    -   alkoxy denotes —O-alkyl;    -   C₁₋₈alkyl denotes a straight chain, branched, or cyclic        hydrocarbon group having from 1 to 8 carbon atoms;    -   C₁₋₈alkenyl denotes a straight chain, branched, or cyclic        hydrocarbon group having from 1 to 8 carbon atoms and at least        one double bond;    -   alkyl, other than C₁₋₈alkyl, denotes methyl, ethyl, n-propyl,        isopropyl, cyclopropyl, n-butyl, sec-butyl, tert-butyl,        cyclobutyl, cylopropylmethyl, n-pentyl, isopentyl, tert-pentyl,        cyclopentyl, cyclotpentylmethyl, n-hexyl, or cyclohexyl.

It is appreciated that compounds of Formula (I) can have one or morechiral centers, and exist as enantiomers or diastereomers. The inventionis to be understood to extend to all such enantiomers, diastereomers andmixtures thereof, including racemates. Formula (I) and the formulaehereinafter are intended to represent all individual isomers andmixtures thereof, unless stated or shown otherwise.

It is also appreciated that certain features of the invention, whichare, for clarity, described in the context of separate embodiments, mayalso be provided in combination in a single embodiment Conversely,various features of the invention, which are, for brevity, described inthe context of a single embodiment, may also be provided separately orin any suitable subcombination. All combinations of the embodimentspertaining to the chemical groups represented by the variables (e.g. R₁,R₂, R_(2a), R₃, R₄, R₅, R₆, etc.) contained within the generic chemicalformulae described herein ([e.g. Formula (I) etc.] are specificallyembraced by the present invention just as if they were explicitlydisclosed, to the extent that such combinations embrace compounds thatresult in stable compounds (ie., compounds that can be isolated,characterized and tested for biological activity). In addition, allsubcombinations of the chemical groups listed in the embodimentsdescribing such variables, as well as all subcombinations of uses andmedical indications described herein, are also specifically embraced bythe present invention just as if each of such subcombination of chemicalgroups and subcombination of uses and medical indications wereexplicitly disclosed herein.

As used herein, “substituted” indicates that at least one hydrogen atomof the chemical group is replaced by a non-hydrogen substituent orgroup, the non-hydrogen substituent or group can be monovalent ordivalent. When the substituent or group is divalent, then it isunderstood that this group is further substituted with anothersubstituent or group. When a chemical group herein is “substituted” itmay have up to the full valance of substitution; for example, a methylgroup can be substituted by 1, 2, or 3 substituents, a methylene groupcan be substituted by 1 or 2 substituents, a phenyl group can besubstituted by 1, 2, 3, 4, or substituents, a naphthyl group can besubstituted by 1, 2, 3, 4, 5, 6, or 7 substituents and the like.Likewise, “substituted with one or more substituents” refers to thesubstitution of a group with one substituent up to the total number ofsubstituents physically allowed by the group. Further, when a group issubstituted with more than one group they can be identical or they canbe different.

As used herein, the term “alkyl” is intended t denote hydrocarbon groupsincluding straight chain, branched and cyclic hydrocarbons, includingfor example but not limited to methyl, ethyl, n-propyl, isopropyl,cyclopropyl, n-butyl, sec-butyl, tert-butyl, cyclobutyl,cyclopropylmethyl, n-pentyl, isopentyl, tert-pentyl, cyclopentyl,cyclopentylmethyl, n-hexyl, cyclohexyl, and the like. Throughout thisspecification, it should be understood that the term alkyl is intendedto encompass both non-cyclic hydrocarbon groups and cyclic hydrocarbongroups. In some embodiments of the compounds of the invention, alkylgroups are non-cyclic. In further embodiments, alkyl groups are cyclic,and in further embodiments, alkyl groups are both cyclic and noncyclic.Where no preference is specified, the term “alkyl” is intended to denotegroups that are both cyclic and non-cyclic.

As used herein, the term “alkenyl” is intended to denote hydrocarboncompounds including straight chain, branched and cyclic hydrocarbonsthat contain at least one double bond, including for example but notlimited to allyl, 2-methyl-allyl, 4-but-3-enyl, 4-hex-5-enyl,3-methyl-but-2-enyl, cyclohex-2-enyl and the like.

As used herein, the term “halogen” has its normal meaning of periodseven elements, including F, Cl, Br and I.

The term “alkoxy” is intended to denote substituents of the formula—O-alkyl, including —O-allyl. The term “lower” when used in connectionwith substituents such as alkyl indicates 6 carbons or less.

The term “arylalkyl” or “aralkyl” is intended to denote an alkyl groupthat bears an aryl substituent, for example a benzyl group. The term“alkylaryl” or “alkaryl” is intended to denote an aryl group that bearsan alkyl substituent, for example a 4-methylphenyl group.

As used herein, the term “aryl” is intended to mean monocyclic andpolycyclic aromatic groups. Although aryl groups can include as few as 3carbon atoms, preferred aryl groups have 6 to about 14 carbon atoms,more preferably 6 to about 10 carbon atoms. Examples of aryl groupsinclude but are not limited to phenyl, naphthyl, anthracyl, phenanthryland pyrenyl.

The term “heteroaryl” is Intended to denote an aryl group that containsat least one, and preferably from one to four ring “hetero” (i.e.,non-carbon, e.g., O, N or S) atom. Examples of “heteroaryl” groups areradicals derived from 5- and 6-member aryl ring compounds having fromone to four nitrogen, sulfur and/or oxygen atoms, for example pyrrole,pyrazole, imidazole, triazole, tetrazole, pyridine, pyrimidine, furan,pyran, thiophene, benzimidazole, quinoline, isoquinoline, oxazole,thiazole, and thiadiazole.

As used herein the term heteroarylalkyl means an alkyl group that bearsa heteroaryl substituent, for example a group having the structure—CH₂-pyrrole-2-yl.

The term “substituted thiazole” means a radical derived from thiazolethat bears at least one substituent group. The term “thiazolederivative” means a fused ring system in which one of the fused rings isthiazole.

The term “substituted imidazole” means a radical derived from imidazolethat bears at least one substituent group. The term “imidazolederivative” means a fused ring system in which one of the fused rings isimidazole.

Certain substituents of the compounds disclosed herein can optionally besubstituted, i.e., they can optionally bear further substituent groups.Some preferred substituent groups include halogen, lower alkyl(including but not limited to methyl, ethyl, isopropyl, cyclopropyl,tert-butyl, and methylcyclopropyl), alkoxy, mono-, di- or trihaloalkoxy(e.g., —O—CX₃ where X is halogen), —(CH₂)_(y)NH₂, —(CH₂)_(y)NHBoc,—N(R_(4a))(R_(4b)), phenyl, methoxyphenyl and naphthyl.

At various places in the present specification substituents of compoundsof the invention are disclosed in groups or in ranges. It isspecifically intended that the invention include each and everyindividual subcombination of the members of such groups and ranges. Forexample, the term “C₁₋₈ alkyl” is specifically intended to individuallydisclose methyl, ethyl, C₃ alkyl, C₄ alkyl, C₅ alkyl, C₆ alkyl, C₇ alkyland C₈ alkyl.

Additionally, compounds of the present invention encompass allpharmaceutically acceptable salts, solvates, and particularly hydrates,thereof; including but not limited to, phentermine, phenterminederivatives (e.g., chlorphentermine), selective 5HT-2C receptor agonists(e.g., compounds of Formula (I)), and the like.

In some embodiments of the present invention, the selective 5HT-2Creceptor agonist is of Formula (I): wherein:

-   -   R₃ is halogen, perhaloalkyl, CN, SR₅, NHR₅, N(R₅)₂, aryl, or        heteroaryl, wherein said aryl can be optionally substituted with        up to two substituents selected from C₁₋₈ alkyl, halogen,        perhalo alkyl, and alkoxy, and said heteroaryl can be optionally        substituted with up to two substituents selected from halogen        and C₁₋₈ alkyl; and    -   R₄ is H, halogen, perhaloalkyl, CN, SR₅, NHR₅, N(R₅)₂, aryl, or        heteroaryl, wherein said aryl can be optionally substituted with        up to two substituents selected from C₁₋₈ alkyl, halogen,        perhalo alkyl, and alkoxy, and said heteroaryl can be optionally        substituted with up to two substituents selected from halogen        and C₁₋₈ alkyl;    -   wherein heteroaryl is pyrrolyl, pyrazolyl, imidazolyl,        triazolyl, tetrazolyl, pyridyl, pyrimidinyl, furanyl, pyranyl,        thienyl, benzimidazolyl, quinolinyl, isoquinolinyl, oxazolyl,        thiazolyl or thiadiazolyl.

In some embodiments of the present invention, the selective 5HT-2Creceptor agonist is of Formula (I) wherein R₁ is H.

In some embodiments of the present invention, the selective 5HT-2Creceptor agonist is of Formula (I) wherein R₁ is methyl.

In some embodiments of the present invention, the selective 5HT-2Creceptor agonist is of Formula (I) wherein R₂ is methyl, ethyl, n-propylor isopropyl.

In some embodiments of the present invention, the selective 5HT-2Creceptor agonist is of Formula (I) wherein R₂ is methyl or ethyl.

In some embodiments of the present invention, the selective 5HT-2Creceptor agonist is of Formula (I) wherein R₂ and R_(2a) together form—CH₂CH₂—.

In some embodiments of the present invention, the selective 5HT-2Creceptor agonist is of Formula (I) wherein R₃ is chlorine.

In some embodiments of the present invention, the selective 5HT-2Creceptor agonist is of Formula (I) wherein R₃ is bromine.

In some embodiments of the present invention, the selective 5HT-2Creceptor agonist is of Formula (I) wherein R₃ is perhaloalkyl. In someembodiments, R₃ is CF₃.

In some embodiments of the present invention, the selective 5HT-2Creceptor agonist is of Formula (I) wherein R₃ is selected from the groupconsisting of thienyl, furanyl, pyrrolyl, pyrazolyl and imidazolyl.

In some embodiments of the present invention, the selective 5HT-2Creceptor agonist is of Formula (I) wherein R₄ is selected from the groupconsisting of thienyl, furanyl, pyrrolyl, pyrazolyl and imidazolyloptionally substituted with one or two substituents selected fromhalogen or methyl or wherein R₄ is phenyl optionally substituted with upto two substituents selected from C₁₋₈ alkyl, halogen, and alkoxy.

In some embodiments of the present Invention, the selective 5HT-2Creceptor agonist is of Formula (I) wherein: R₂ is methyl, ethyl,isopropyl, or CH₂OH; or R₂ and R_(2a) taken together form —CH₂CH₂—.

In some embodiments of the present invention, the selective 5HT-2Creceptor agonist is of Formula (I) wherein: R₃ is halogen, or a5-membered heteroaryl ring having up to two heteroatoms selected from O,N and S, and up to two substituents selected from halogen and C₁₋₈alkyl.

In some embodiments of the present invention, the selective 5HT-2Creceptor agonist is of Formula (I) wherein: R₄ is H, a 5-memberedheteroaryl ring having up to two heteroatoms selected from O, N and Sand up to two substituents selected from halogen and C₁₋₈ alkyl, orphenyl optionally substituted with up to two substituents selected fromC₁₋₈ alkyl, halogen, and alkoxy.

In some embodiments of the present invention, the selective 5HT-2Creceptor agonist is of Formula (I) wherein: R₆ is H or methyl.

In some embodiments of the present invention, the selective 5HT-2Creceptor agonist is of Formula (I) wherein: R₁ is H.

In some embodiments of the present invention, the selective 5HT-2Creceptor agonist is of Formula (I) wherein: R₂ methyl.

In some embodiments of the present invention, the selective 5HT-2Creceptor agonist is of Formula (I) wherein: R₃ is chlorine, bromine, orthenyl.

In some embodiments of the present invention, the selective 5HT-2Creceptor agonist is of Formula (I) wherein: R₄ is pyrazolyl-3-yl orphenyl wherein said pyrazolyl-3-yl optionally has up to two substituentsselected from halogen and C₁₋₈ alkyl, and said phenyl optionally has asingle halogen substitutent.

In some embodiments of the present invention, the selective 5HT-2Creceptor agonist is of Formula (I) wherein: R₆ is H.

In some embodiments of the present invention, the selective 5HT-2Creceptor agonist is of Formula (I) wherein: R₁ is H or Me.

In some embodiments of the present invention, the selective 5HT-2Creceptor agonist is of Formula (I) wherein: R₂ is Me, Et, or OH.

In some embodiments of the present invention, the selective 5HT-2Creceptor agonist is of Formula (I) wherein: R_(2a) is H.

In some embodiments of the present invention, the selective 5HT-2Creceptor agonist is of Formula (I) wherein: R₃ is F, Cl, Br, I, CF₃, or2-chlorophenyl.

In some embodiments of the present invention, the selective 5HT-2Creceptor agonist is of Formula (I) wherein: R₁ is H.

In some embodiments of the present invention, the selective 5HT-2Creceptor agonist is of Formula (I) wherein: R₆ is H.

In some embodiments of the present invention, the selective 5HT-2Creceptor agonist is of Formula (I) wherein: R₁ is H.

In some embodiments of the present invention, the selective 5HT-2Creceptor agonist is of Formula (I) wherein: R₂ is C₁₋₈ alkyl.

In some embodiments of the present invention, the selective 5HT-2Creceptor agonist is of Formula (I) wherein: R_(2a) is H.

In some embodiments of the present invention, the selective 5HT-2Creceptor agonist is of Formula (I) wherein: R₃ is halogen.

In some embodiments of the present invention, the selective 5HT-2Creceptor agonist is of Formula (I) wherein: R₄ is H.

In some embodiments of the present invention, the selective 5HT-2Creceptor agonist is of Formula (I) wherein: R₆ is H.

The invention provides a composition comprising phentermine and aselective 5HT-2C receptor agonist as described herein wherein saidselective 5HT-2C receptor agonist is selected from the group consistingof:

-   8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine;-   8-bromo-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine;-   8-iodo-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine;-   8-trifluoromethyl-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine;-   8-trifluoromethyl-1-ethyl-2,3,4,5-tetrahydro-1H-3-benzazepine;-   8-chloro-1-ethyl-2,3,4,5-tetrahydro-1H-3-benzazepine;-   8-bromo-1-ethyl-2,3,4,5-tetrahydro-1H-3-benzazepine;-   8-iodo-1-ethyl-2,3,4,5-tetrahydro-1H-3-benzazepine;-   7,8-dichloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine;-   7,8-dichloro-1-ethyl-2,3,4,5-tetrahydro-1H-3-benzazepine;-   8-chloro-7-fluoro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine;-   8-chloro-7-methoxy-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine; and-   8-chloro-7-fluoro-1-ethyl-2,3,4,5-tetrahydro-1H-3-benzazepine;    -   or a pharmaceutically acceptable salt, solvate or hydrate        thereof.

The compounds of the invention may contain one or more asymmetric carbonatoms, so that the compounds can exist in different stereoisomericforms. The compounds can be, for example, racemates or optically activeforms. The optically active forms can be obtained by resolution of theracemates or by asymmetric synthesis. In some embodiments, compounds ofFormula (I) are R enantiomers. In some embodiments, compounds of Formula(I) are S enantiomers. In some embodiments, compounds of Formula (I) arevarying mixtures of enantiomers.

In one embodiment, the invention provides a composition comprisingphentermine and a selective 5HT-2C receptor agonist wherein saidselective 5HT-2C receptor agonist is(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof.

The compounds and compositions according to the invention may optionallyexist as pharmaceutically acceptable salts including pharmaceuticallyacceptable acid addition salts prepared from pharmaceutically acceptablenon-toxic acids including inorganic and organic acids. Such acidsinclude acetic, benzenesulfonic, benzoic, camphorsulfonic, citric,ethenesulfonic, dichloroacetic, formic, fumaric, gluconic, glutamic,hippuric, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic,mandelic, methanesulfonic, mucic, nitric, oxalic, pamoic, pantothenic,phosphoric, succinic, sulfuric, tartaric, oxalic, p-toluenesulfonic andthe like, such as the pharmaceutically acceptable salts listed inJournal of Pharmaceutical Science, 66, 2 (1977) and incorporated hereinby reference.

The acid addition salts can be obtained as the direct products ofcompound synthesis. In the alternative, the free base can be dissolvedin a suitable solvent containing the appropriate acid, and the saltisolated by evaporating the solvent or otherwise separating the salt andsolvent. The compounds of this invention may form solvates with standardlow molecular weight solvents using methods known to the skilledartisan.

Compositions of the invention may conveniently be administered in unitdosage form and can be prepared by any of the methods well known in thepharmaceutical art, for example, as described in Remington'sPharmaceutical Sciences (Mack Pub. Co., Easton, Pa., 1980).

The invention also provides compositions of the invention, as describedabove, further comprising a pharmaceutically acceptable carrier. Forexample, the invention provides a composition comprising phentermine and(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine, or apharmaceutically acceptable salt, solvate or hydrate thereof, and apharmaceutically acceptable carrier. Thus, the invention providespharmaceutical compositions containing phentermine and a selective5HT-2C agonist. A pharmaceutical composition is a composition comprisingat least one active ingredient and at least one ingredient that is notan active ingredient (for example and not limitation, a filler, dye, ora mechanism for slow release), whereby the composition is amenable touse for a specified, efficacious outcome in a mammal (for example, andnot limitation, a human).

According to a further aspect of the invention, the compositions of theinvention are provided for use in therapy. The compositions can be usedin the prophylaxis or treatment of disorders associated with 5-HT_(2C)receptor function.

According to a further aspect of the invention, there is provided use ofa composition of the invention in the manufacture of a medicament forthe prophylaxis or treatment of the disorders disclosed herein. In apreferred embodiment, there is provided a use of a composition of theinvention in the manufacture of a medicament for the prophylaxis ortreatment of obesity.

The data developed herein supports the conclusion that the presentlydisclosed compositions of the invention are of use for the treatment orprophylaxis of clinical obesity or overweight disorders in mammals,including, but not limited to, human. Compositions of the presentinvention can be administered by oral, sublingual, parenteral, rectal,topical administration or by a transdermal patch. Transdermal patchesdispense a drug at a controlled rate by presenting the drug forabsorption in an efficient manner with a minimum of degradation of thedrug. Typically, transdermal patches comprise an impermeable backinglayer, a single pressure sensitive adhesive and a removable protectivelayer with a release liner. One of ordinary skill in the art willunderstand and appreciate the techniques appropriate for manufacturing adesired efficacious transdermal patch based upon the needs of theartisan.

In addition to the neutral forms of compositions of the presentinvention, by appropriate addition of an ionizable substituent, whichdoes not alter the receptor specificity of the compound, physiologicallyacceptable salts of the compositions may also be formed and used astherapeutic agents. Different amounts of the compositions of the presentinvention will be required to achieve the desired biological effect. Theamount will depend on factors such as the specific composition, the usefor which it is intended, the means of administration, and the conditionof the treated individual—all of these dosing parameters are within thelevel of one of ordinary skill in the medicinal arts. A typical dose canbe expected to fall in the range of 0.001 to 200 mg per kilogram of bodyweight of the mammal. For example a typical dose can fall in the rangeof 0.001 to 0.01, 0.01 to 0.1, 0.1 to 1, 1 to 10, 10 to 100, or 100 to200 mg per kilogram of body weight of the mammal. Unit doses may containfrom 1 to 200 mg of the compositions of the present invention and can beadministered one or more times a day, individually or in multiples. Forexample, unit doses can contain from 1 to 10, 10 to 50, 50 to 100, 100to 150 or 150 to 200 mg of the compositions of the invention and can beadministered one or more times a day, individually or in multiples.

The compositions of the present invention can be combined with thecarrier in either solid or liquid form in a unit dose formulation. Thepharmaceutical carrier must be compatible with the other ingredients inthe composition and must be tolerated by the individual recipient. Otherphysiologically active ingredients can be incorporated into thepharmaceutical composition of the invention if desired, and if suchingredients are compatible with the other ingredients in thecomposition. Formulations can be prepared by any suitable method,typically by uniformly mixing the active compound(s) with liquids orfinely divided solid carriers, or both, in the required proportions, andthen, if necessary, forming the resulting mixture into a desired shape.

Conventional excipients, such as binding agents, fillers, acceptablewetting agents, tabletting lubricants, and disintegrants can be used intablets and capsules for oral administration. Liquid preparations fororal administration can be in the form of solutions, emulsions, aqueousor oily suspensions, and syrups. Alternatively, the oral preparationscan be in the form of dry powder that can be reconstituted with water oranother suitable liquid vehicle before use. Additional additives such assuspending or emulsifying agents, non-aqueous vehicles (including edibleoils), preservatives, and flavorings and colorants can be added to theliquid preparations. Parenteral dosage forms can be prepared bydissolving the compound of the invention in a suitable liquid vehicleand filter sterilizing the solution before filling and sealing anappropriate vial or ampoule. These are just a few examples of the manyappropriate methods well known in the art for preparing dosage forms.

It is noted that the compositions of the invention are not intended foruse only in humans, but in other non-human mammals as well. Indeed,recent advances in the area of animal health-care mandate thatconsideration be given for the use of compositions of the invention forthe treatment of obesity in domestic animals (e.g., cats and dogs), andin other domestic animals where no disease or disorder is evident (e.g.,food-oriented animals such as cows, chickens, fish, etc.). Those ofordinary skill in the art are readily credited with understanding theutility of such compositions in such settings.

The selective 5HT-2C receptor agonists of Formula (I) in thecompositions can be readily prepared according to a variety of syntheticmanipulations, all of which would be familiar to one skilled in the art.A representative general synthesis is set forth below in Scheme I

Those of skill in the art will appreciate that a wide variety ofselective 5HT-2C receptor agonist compounds described in the inventioncan be prepared according to Scheme I. For example, by starting with anappropriately substituted 2-phenyl ethylamino compound A′ having any ofa wide variety of substituents R₁ and R₂, the corresponding 7- and/or8-substituted 1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine (compound H)can be prepared. N-alkylation can be accomplished by, for example,treatment with excess paraformaldehyde (for methylation) or a higherorder aldehyde, followed by reduction with NaBH₃CN according to thegeneral procedure of synthetic examples 9 and 10, infra. In addition, bystarting with an appropriately substituted 1-alkyl-2-phenyl ethylaminocompound A′ having any of a wide variety of substituents R₁ and R₂, thecorresponding 7- and/or 8-substituted2,5-dialkyl-2,3,4,5-tetrahydro-1H-3-benzazepine compound can beprepared.

In the synthesis of many compounds of the invention, protecting groupscan be required to protect various functionality or functionalitiesduring the synthesis. Representative protecting groups suitable for awide variety of synthetic transformations are disclosed in Greene andWuts, Protective Groups in Organic Synthesis, 2d ed, John Wiley & Sons,New York, 1991, the disclosure of which is incorporated herein byreference in its entirety.

The invention provides a method of decreasing food intake of a mammalcomprising administering to said mammal a pharmaceutically effectiveamount of a combination comprising a selective 5HT-2C receptor agonistand an amount of phentermine, wherein said selective 5HT-2C receptoragonist and phentermine are provided in amounts to give a synergisticeffect in decreasing food intake in said mammal. For example, theinvention provides a method of decreasing food intake of a mammalcomprising administering to said mammal a pharmaceutically effectiveamount of a combination comprising an amount of(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine and an amountof phentermine, wherein said(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine andphentermine are provided in amounts to give a synergistic effect indecreasing food intake in said mammal. In one embodiment, the amount ofselective 5HT-2C receptor agonist, for example,(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine, alone and/orthe amount of phentermine alone are therapeutically effective (i.e.showing a statistically significant effect) in decreasing food intake insaid mammal and the compounds are provided in amounts to give asynergistic effect in decreasing food intake in said mammal.

In one embodiment, the amount of selective 5HT-2C receptor agonist, forexample, (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine,alone and/or the amount of phentermine alone are therapeuticallysub-effective in decreasing food intake in said mammal. As used herein,“therapeutically sub-effective” means that the 5HT-2C agonist and/orphentermine are provided in amounts that do not have a statisticallysignificant effect on the measured parameter. For example, the amount ofselective 5HT-2C receptor agonist, for example,(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine, alone and/orthe amount of phentermine alone can be therapeutically ineffective indecreasing food intake in said mammal. Since the combination of aselective 5HT-2C receptor agonist and phentermine have a synergisticeffect (see, for example, FIG. 2, FIGS. 3A and B, and FIGS. 4A and B),the combination therapy can be therapeutically effective while each ofthe compounds separately are therapeutically sub-effective (whichincludes, for example, when the compound or compounds are ineffective).In a method of treatment, a therapeutically effective dose of thecombination of the selective 5HT-2C receptor agonist and phentermine isused.

The invention also provides a method of inducing satiety in a mammalcomprising administering to said mammal a pharmaceutically effectiveamount of a combination comprising an amount of a selective 5HT-2Creceptor agonist and an amount of phentermine, wherein said selective5HT-2C receptor agonist and phentermine are provided in amounts to givea synergistic effect in inducing satiety in said mammal. For example,the invention provides a method of inducing satiety in a mammalcomprising administering to said mammal a pharmaceutically effectiveamount of a combination comprising an amount of(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine and/or anamount of phentermine, wherein said(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine andphentermine are provided in amounts to give a synergistic effect ininducing satiety in said mammal. In one embodiment, the amount ofselective 5HT-2C receptor agonist, for example,(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine, alone and/orthe amount of phentermine alone are therapeutically sub-effective orineffective in inducing satiety in said mammal.

In addition, the invention provides a method of controlling weight gainof a mammal comprising administering to said mammal a pharmaceuticallyeffective amount of a combination comprising an amount of a selective5HT-2C receptor agonist and an amount of phentermine, wherein saidselective 5HT-2C receptor agonist and phentermine are provided inamounts to give a synergistic effect in controlling weight gain in saidmammal. For example, the invention provides a method of controllingweight gain of a mammal comprising administering to said mammal apharmaceutically effective amount of a combination comprising an amountof (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine and/or anamount of phentermine, wherein said(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine andphentermine are provided in amounts to give a synergistic effect incontrolling weight gain in said mammal. In one embodiment, the amount ofselective 5HT-2C receptor agonist, for example,(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine, alone and/orthe amount of phentermine alone are therapeutically sub-effective orineffective in controlling weight gain in said mammal.

The invention further provides a method of prophylaxis or treatment ofobesity, or a condition related thereto, comprising administering to apatient in need of such prophylaxis or treatment a therapeuticallyeffective amount of a combination comprising an amount of a selective5HT-2C receptor agonist and an amount of phentermine, wherein saidselective 5HT-2C receptor agonist and phentermine are provided inamounts to give a synergistic effect in decreasing food intake in saidmammal. For example, the invention further provides a method ofprophylaxis or treatment of obesity, or a condition related thereto,comprising administering to a patient in need of such prophylaxis ortreatment a therapeutically effective amount of a combination comprisingan amount of (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepineand an amount of phentermine, wherein said(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine andphentermine are provided in amounts to give a synergistic effect indecreasing food intake in said mammal. In one embodiment, the amount ofselective 5HT-2C receptor agonist, for example,(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine, alone and/orthe amount of phentermine alone are therapeutically sub-effective orineffective in decreasing food intake in said mammal. Conditions relatedto obesity include, for example, type II diabetes, atherosclerosis, highblood pressure, syndrome X and the like. In some embodiments thedisorder is obesity.

The invention also provides the above disclosed methods furthercomprising the step of identifying a subject, said subject being in needof prophylaxis or treatment for obesity, or a condition related thereto,wherein said identifying step is performed prior to administering tosaid subject said therapeutically effective amount of said compounds.

One aspect of the present invention pertains to a method for thetreatment of obesity, or a condition related thereto, comprisingadministering to a subject suffering form said condition atherapeutically effective amount of a composition comprising a selective5HT-2C receptor agonist and phentermine, as described herein, preferablyin the form of a pharmaceutical composition.

One aspect of the present invention pertains to a composition comprisinga selective 5HT-2C receptor agonist and phentermine for use in a methodof treatment of the human or animal body by therapy. For example, theinvention provides a composition of the invention for use in a method oftreatment of a 5HT2C disorder of the human or animal body by therapy.The invention also provides a composition of the invention for use in amethod of prophylaxis or treatment of obesity of a mammal, for use in amethod of decreasing food intake of a mammal, for use in a method ofinducing satiety in a mammal, and/or for use in a method of controllingweight gain of a mammal.

One aspect of the present invention pertains to a composition of theinvention for the manufacture of a medicament for use in the propylaxisor treatment of a 5HT2C disorder of the human or animal body by therapy.For example, one aspect of the present invention pertains to acomposition comprising a selective 5HT-2C receptor agonist andphentermine for the manufacture of a medicament for use in thepropylaxis or treatment of obesity, or conditions related thereto. Insome embodiments the disorder is obesity. In addition, for example, theinvention provides a composition of the invention for the manufacture ofa medicament for use in a method of decreasing food intake of a mammal,for the manufacture of a medicament for use in a method of inducingsatiety in a mammal, and/or for the manufacture of a medicament for usein a method of controlling weight gain of a mammal.

In some embodiments, the invention provides methods for alleviation of asymptom of any of the diseases, conditions or disorders mentionedherein.

As will be recognized, the steps of the methods of the present inventionneed not be performed any particular number of times or in anyparticular sequence. Additional objects, advantages, and novel featuresof this invention will become apparent to those skilled in the art uponexamination of the following examples thereof, which are intended to beillustrative and not intended to be limiting.

EXAMPLES Synthetic Examples Example 1(R,S)8-Bromo-7-methoxy-1-methyl-2,3,4,5-tetrahydro-1-3-benzazepine

N-Trifluoroacetyl-3-methoxyphenethylamine

A solution of 3-methoxyphenethylamine (10.0 g, 64.0 mmol) indichloromethane (150 ml), was cooled to 0° C., and treated with pyridine(6.5 mL, 83.5 mmol) followed by the dropwise addition of trifluoraceticanhydride (17.9 g, 83.5 mmol) and the resulting mixture stirred for 3hours while warming to 20° C. The product mixture was diluted with EtOAc(500 mL), washed sequentially with 10% aqueous HCl (100 mL), water (100mL), brine (100 mL), dried with Na₂SO₄ and concentrated to give 15.8 gof a yellow oil. ¹H NMR (400 MHz, CDCl₃) δ 7.26 (dd, J=8, 8 Hz, 1H),6.81 (d, J=8 Hz, 1H), 6.77 (d, J=8 Hz, 1H), 6.72 (s, 1H), 6.30 (bs, 1H),3.80 (s, 3H), 3.62 (dd, J=7, 7 Hz, 2H), 2.86 (dd, J=7, 7 Hz, 2H). MScalculated for C₁₁H₁₂F₃NO₂+H: 248, observed: 248.

N-Trifluoroacetyl-2-iodo-5-methoxyphenethylamine

A solution of N-trifluoroacetyl-3-methoxyphenethylamine (15.8 g, 64mmol) in methanol (325 mL) was cooled to −78° C., and treated with CaCO₃(14.7 g, 145 mmol), followed by a solution of ICl (29 g, 181 mmol) inmethanol (40 mL). The reaction was allowed to warm to 20° C. whilestirring overnight and then filtered, concentrated, dissolved in EtOAc(200 mL), washed twice with 5% aqueous sodium bisulfite (100 mL), oncewith brine (100 mL), dried with Na₂SO₄ and concentrated to give 23.8 gof a white solid powder. ¹H NMR (400 MHz, CDCl₃) δ 7.68 (d, J=9 Hz, 1H),6.76 (s, 1H), 6.57 (d, J=9 Hz, 1H), 6.42 (bs, 1H), 3.77 (s, 3H), 3.61(dd, J=7, 7 Hz, 2H), 2.99 (dd, J=7, 7 Hz, 2H). MS calculated forC₁₁H₁₁F₃INO₂+H: 374, observed: 374.

N-Allyl, N-trifluoroacetyl-2-iodo-5-methoxyphenethylamine

A solution of N-trifluoroacetyl-2-iodo-5-methoxyphenethylamine (23.8 g,63.8 mmol) in toluene (425 mL) was sequentially treated with K₂CO₃ (12.4g, 89.8 mmol), KOH (11.6 g, 207 mmol), n-Bu₄NBr (2.2 g, 6.9 mmol) andallyl bromide (10.7 g, 89.8 mmol). The mixture was stirred at 80° C. for3.5 hours, cooled to 20° C., acidified with 10% aqueous HCl, separatedand the aqueous phase extracted with ether (500 mL). The combinedorganic phases were washed with brine (200 mL), dried with Na₂SO₄ andconcentrated to give 20.5 g of a brown oil. ¹H NMR (400 MHz, CDCl₃),mixture of rotamers d 7.67 (m, 1H), 6.80 (m, 1H), 6.57 (m, 1H), 5.9-5.6(bm, 1H), 5.27 (m, 2H), 4.11 (d, J=6 Hz, 0.5H), 3.85 (d, J=6 Hz, 0.5H),3.77 (m, 3H), 3.55 (m, 2H), 3.00 (m, 2H). MS calculated forC₁₄H₁₅F₃INO₂+H: 414, observed: 414.

N-Trifluoroacetyl-7-methoxy-1-methylene-2,3,4,5-tetrahydro-1H-3-benzazepine

A solution of N-allyl, N-trifluoroacetyl-2-iodo-5-methoxyphenethylamine(20.5 g, 50 mmol) in dimethylformamide (250 mL) is treated with KOAc(14.6 g, 149 mmol), n-Bu₄NBr (16.0 g, 50 mmol), PPh₃ (1.3 g, 5.0 mmol),Pd(OAc)₂ (0.56 g, 2.5 mmol) and stirred overnight at 90° C. The productmixture was cooled to 20° C., filtered, diluted with water (500 mL) andextracted with ether (3×500 mL). The combined organic phases were washedwith water (100 mL), brine (100 mL), dried with Na₂SO₄ and concentrated.Flash chromatography (10% EtOAc in hexane, silica) resulted in 6.6 g ofa yellow oil. ¹H NMR (400 MHz, CDCl₃) δ 7.26 (d, J=8 Hz, 1H), 6.77 (d,J=8 Hz, 1H), 6.66 (s, 1H), 5.34-5.19 (m, 2H), 4.40 (m, 2H), 3.83 (m,2H), 3.80 (s, 3H), 3.00 (m, 2H). MS calculated for C₁₄H₁₄F₃NO₂+H: 285,observed: 285.

N-Trifluoroecetyl-7-methoxy-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine

A solution ofN-trifluoroacetyl-7-methoxy-1-methylene-2,3,4,5-trihydro-1H-3-benzazepine(6.6 g, 23.2 mmol) in ethanol (100 mL), was treated with 10% Pd/C (0.75g, 2.3 mmol) and stirred overnight under an atmosphere of hydrogen. Theproduct mixture was filtered through a pad of celite and silica and thesolvent removed to give 6.27 g of a white solid. ¹H NMR (400 MHz, CDCl₃,mixture of rotamers) δ 7.10 (m, 1H), 6.74 (m, 1H), 6.68 (m, 1H), 4.1-3.8(bm, 2H), 3.8 (s, 3H), 3.5 (m, 1.5H), 3.4 (m, 0.5H), 3.2-2.9 (bm, 4H),1.32 (m, 3H). MS calculated for C₁₄H₁₆F₃NO₂+H: 288, observed: 288.

N-Trifluoroacetyl-8-bromo-7-methoxy-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine

A solution ofN-trifluoroacetyl-7-methoxy-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine(1.25 g, 4.35 mmol) in acetonitrile (40 mL) was treated withN-bromosuccinimide (0.852 g, 4.79 mmol) and stirred overnight at 20° C.The product mixture was diluted with EtOAc (200 mL), washed withsaturated aqueous sodium bisulfite (100 mL) and brine (100 mL), driedwith Na₂SO₄ and concentrated. Flash chromatography (15% EtOAc in hexane,silica) resulted in 1.55 g of a clear oil. ¹H NMR (400 MHz, CDCl₃,mixture of rotamers) δ 7.34 (s, 1H), 6.65 (m, 1H), 3.87 (s, 3H), 3.81(m, 1H), 3.55 (m, 1.3H), 3.37 (m, 0.7H), 3.2-2.9 (bm, 4H), 1.30 (m, 3H).MS calculated for C₁₄H₁₅BrF₃NO₂+H: 366, observed: 366.

8-Bromo-7-methoxy-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine

A solution ofN-trifluoroacetyl-8-bromo-7-methoxy-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine(0.95 g, 2.59 mmol) in methanol (20 mL) was treated with 15% aqueousNaOH (25 mL), and stirred overnight at 20° C. The product mixture wasdiluted with water (100 mL), extracted twice with EtOAc (100 mL), thecombined organic phases were washed with brine (100 mL), dried withNa₂SO₄ and concentrated to give 0.687 g of a clear oil. ¹H NMR (400 MHz.CDCl₃) δ 7.92 (s, 1H), 6.34 (s, 1H), 3.87 (s, 3H), 3.1-2.9 (m, 6H), 2.75(m, 1H), 2.60 (bs, 1H), 1.31 (d, J=7 Hz, 3H). MS calculated forC₁₂H₁₆BrNO+H: 270, observed: 270.

Example 2(R,S)8-Chloro-7-methoxy-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine

N-Trifluoroacetyl-8-chloro-7-methoxy-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine

A solution ofN-trifluoroacetyl-7-methoxy-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine(0.900 g, 2.67 mmol) in acetonitrile (30 mL) was treated withN-chlorosuccinimide (0.357 g, 2.67 mmol) and stirred overnight at 70° C.The product mixture was diluted with water (100 mL), extracted twicewith EtOAc (100 mL), the combined organic phases washed with brine (100mL), dried with Na₂SO₄ and concentrated. Flash chromatography (20% EtOAcin hexane, silica) resulted in 0.399 g of a clear oil. ¹H NMR (400 MHz,CDCl₃, mixture of rotamers) δ 7.17 (s, 1H), 6.68 (m, 1H), 3.88 (s, 3H),3.78 (m, 1H), 3.6-3.3 (m, 2H), 3.2-2.9 (m, 4H), 1.34 (m, 3H). MScalculated for C₁₄H₁₅CIFaNO₂+H: 322, observed: 322.

8-Chloro-7-methoxy-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine

A solution ofN-trifluoroacetyl-8-chloro7-methoxy-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine(0.399 g, 1.24 mmol) in methanol (20 mL) was treated with 15% aqueousNaOH (20 mL), and stirred overnight at 20° C. The product mixture wasdiluted with water (100 mL), extracted twice with EtOAc (100 mL), thecombined organic phases were washed with brine (100 mL), dried withNa₂SO₄ and concentrated to give 0.306 g of a yellow solid. ¹H NMR (400MHz, CDCl₃) δ 7.05 (s, 1H), 6.59 (s, 1H), 3.80 (s, 3H), 3.0-2.8 (m, 6H),2.62 (m, 1H), 2.16 (bs, 1H), 1.24 (d, J=7 Hz, 3H). MS calculated forC₁₂H₁₆ClNO+H: 226, observed: 226.

Example 3(R,S)8-iodo-7-methoxyl-methyl-2,3,4,5-taetrhydro-1H-3-benzazepine

N-Trifluoroacetyl-8-iodo-7-methoxy-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine

A solution ofN-trifluoroacetyl-7-methoxy-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine(1.50 g, 5.22 mmol) in methanol (70 mL) was treated with CaCO₃ (1.06 g,10.44 mmol) followed by a solution of ICl (1.70 g, 10.44 mmol) inmethanol (10 mL), and stirred overnight at 20° C. The product mixturewas filtered, concentrated, dissolved in EtOAc (200 mL), extracted twicewith 5% aqueous sodium bisulfite (100 mL), once with brine (100 mL),dried with Na₂SO₄ and concentrated. Flash chromatography (15% EtOAc inhexane, silica) resulted in 1.54 g of a white solid. ¹H NMR (400 MHz,CDCl₃, mixture of rotamers) δ 7.55 (m, 1H), 6.57 (m, 1H), 3.86 (s, 3H),3.80 (m, 1H), 3.60-3.30 (m, 2H), 3.20-2.80 (m, 4H), 1.30 (m, 3H). MScalculated for C₁₄H₁₅F₃INO₂+H: 414, observed: 414.

8-Iodo-7-methoxy-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine

A solution ofN-trifluoroacetyl-8-iodo7-methoxy-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine(0.600 g, 1.45 mmol) in methanol (20 mL) was treated with 15% aqueousNaOH (20 mL), and stirred for 3 hours at 50° C. The product mixture wasdiluted with water (100 mL), extracted twice with EtOAc (100 mL), thecombined organic phases were washed with brine (100 mL), dried withNa₂SO₄ and concentrated to give 0.425 g of a yellow solid. ¹H NMR (400MHz, CDCl₃) δ 7.52 (s, 1H), 6.57 (s, 1H), 3.86 (s, 3H), 3.12-3.06 (m,4H), 2.95 (m, 2H), 2.75 (m, 1H), 2.43 (bs, 1H), 1.33 (d, J=8 Hz, 3H). MScalculated for C₁₂H₁₆INO+H: 318, observed: 318.

Example 4(R,S)8-Bromo-7-hydroxy-1-methyl-2,3,4,5-tetrahydro-1H*3-benzazepine

N-Trifluoroacetyl-8-bromo-7-hydroxy-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine

A solution ofN-trifluoroacetyl-8-bromo-7-methoxy-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine(1.50 g, 4.10 mmol) in dichloromethane (80 mL) was treated dropwise withBBr₃ (9.4 mL of a 11.0M solution in CH₂Cl₂, 9.4 mmol), and the mixturestirred overnight while warming to 20° C. The excess BBr₃ was quenchedwith the dropwise addition of water, the mixture diluted with ether (200mL), washed with Na₂CO₃ (100 mL) and brine (100 mL), dried with Na₂SO₄and concentrated. Flash chromatography (15% EtOAc in hexane, silica)resulted in 1.25 g of a white solid foam. ¹H NMR (400 MHz, CDCl₃,mixture of rotamers) δ 7.25 (s, 1H), 6.79 (m, 1H), 3.79 (m, 1H), 3.7-3.3(m, 2H), 3.2-2.8 (m, 4H), 1.32 (m, 3H).

8-Bromo-7-hydroxy-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine

A solution ofN-trifluoroacetyl-8-bromo-7-hydroxy-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine(0.655 g, 1.89 mmol) in methanol (20 mL) was treated with 15% aqueousNaOH (20 mL), and stirred overnight at 20° C. The product mixture wasdiluted with water (100 mL), extracted twice with EtOAc (100 mL), thecombined organic phases were washed with brine (100 mL), dried withNa₂SO₄ and concentrated to give 0.460 g of a clear oil. ¹H NMR (400 MHz,DMSO-d₆) δ 7.11 (s, 1H), 6.65 (s, 1H), 2.90 (m, 1H), 2.73 (m, 5H), 2.55(m, 1H), 1.19 (d, J=7 Hz, 3H). MS calculated for C₁₁H₁₄BrNO+H: 256,observed: 256.

Example 5(R,S)7-Allyloxy-8-bromo-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine

N-Trifluoroacetyl-7-allyloxy-8-bromo-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine

A solution ofN-trifluoroacetyl-8-bromo-7-hydroxy-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine(0.150 g, 0.426 mmol) in dichloromethane (5 mL) was treated with allylbromide (0.155 g, 1.28 mmol) and DBU (0.195 g, 1.28 mmol) and thenstirred 2 hours at 20° C. The product mixture was diluted with EtOAc (50mL), washed with 5% aqueous HCl (20 mL), brine (20 mL), dried withNa₂SO₄ and concentrated. Flash chromatography (15% EtOAc in hexane,silica) resulted in 0.149 g of a clear oil. ¹H NMR (400 MHz, CDCl₃,mixture of rotamers) δ 7.34 (s, 1H), 6.65 (m, 1H), 6.04 (m, 1H), 5.47(d, J=17 Hz, 1H), 5.30 (d, J=9 Hz, 1H), 4.59 (s, 2H), 3.80 (m, 1H),3.6-3.3 (m, 3H), 3.2-2.8 (m, 4H), 1.31 (m, 3H). MS calculated forC₁₆H₁₇BrF₃NO₂+H: 392, observed: 392.

7-Allyloxy-8-bromo-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine

A solution ofN-trifluoroacetyl-7-allyloxy-8-bromo-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine(1.18 g, 3.00 mmol) in methanol (35 mL) was treated with 15% aqueousNaOH (35 mL), and stirred overnight at 20° C. The product mixture wasdiluted with water (200 mL), extracted twice with EtOAc (200 mL), thecombined organic phases were washed with brine (100 mL), dried withNa₂SO₄ and concentrated to give 0.880 g of a clear oil. ¹H NMR (400 MHz.CDCl₃) δ 7.29 (s, 1H), 6.63 (s, 1H), 6.04 (m, 1H), 5.47 (d, J=17 Hz,1H), 5.29 (d, J=11 Hz, 1H), 4.58 (s, 2H), 3.01 (m, 3H), 2.89 (m, 3H),2.75 (m, 1H), 1.31 (d, J=7 Hz, 3H). MS calculated for C₁₄H₁₈BrNO+H: 296,observed: 296.

Example 6(R,S)7-Benzyloxy-8-bromo-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine

N-Trifluoroacetyl-7-benzyloxy-8-bromo-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine

A solution ofN-trifluoroacetyl-8-bromo-7-hydroxy-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine(0.075 g, 0.213 mmol) in dichloromethane (5 mL) was treated with benzylbromide (0.072 g, 0.64 mmol), DBU (0.100 g, 0.64 mmol), and stirred 2hours at 20° C. The product mixture was diluted with EtOAc (50 mL),washed with 5% aqueous HCl (20 mL), brine (20 mL), dried with Na₂SO₄ andconcentrated. Flash chromatography (15% EtOAc in hexane, silica)resulted in 0.081 g of a clear oil. MS calculated for C₂₀H₁₉BrF₃NO₂+H:442, observed: 442.

7-Benzyloxy-8-bromo-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine

A solution ofN-trifluoroacetyl-7-benzyloxy-8-bromo-1-ethyl-2,3,4,5-tetrahydro-1H-3-benzazepine(0.81 g, 1.83 mmol) in methanol (20 mL) was treated with 15% aqueousNaOH (20 mL), and stirred overnight at 20° C. The product mixture wasdiluted with water (200 mL), extracted twice with EtOAc (200 mL), thecombined organic phases were washed with brine (100 mL), dried withNa₂SO₄ and concentrated to give 0.412 g of a clear oil. ¹H NMR (400 MHz,CDCl₃) δ 7.38 (d, J=8 Hz, 2H), 7.30 (dd, J=7, 8 Hz, 2H), 7.23 (m, 2H),6.61 (s, 1H), 5.03 (s, 2H), 2.94 (m, 3H), 2.81 (m, 3H), 2.62 (m, 1H),2.30 (bs, 1H), 1.24 (d, J=7 Hz, 3H). MS calculated for C₁₈H₂₀BrNO+H:346, observed: 346.

Example 7(R,S)8-Bromo-7-ethoxy-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine

N-Trifluoroacetyl-8-bromo-7-ethoxy-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine

A solution ofN-trifluoroacetyl-8-bromo-7-hydroxy-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine(0.015 g, 0.043 mmol) in dichloromethane (1 mL) was treated with ethyliodide (0.016 g, 0.102 mmol), DBU (0.016 g, 0.102 mmol) and stirred 2hours at 20° C. The product mixture was diluted with EtOAc (10 mL),washed with 5% aqueous HCl (5 mL), brine (5 mL), dried with Na₂SO₄ andconcentrated. Flash chromatography (15% EtOAc in hexane, silica)resulted in 0.010 g of a clear oil.

8-Bromo-7-ethoxy-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine

A solution ofN-trifluoroacetyl-8-bromo-7-ethoxy-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine(0.010 g, 0.026 mmol) in methanol (1 mL) was treated with 15% aqueousNaOH (1 mL), and stirred overnight at 20° C. The product mixture wasdiluted with water (3 mL), extracted twice with EtOAc (5 mL), thecombined organic phases were washed with brine (3 mL), dried with Na₂SO₄and concentrated to give 0.007 g of a clear oil. ¹H NMR (400 MHz, CDCl₃)δ 7.29 (s, 1H), 6.63 (s, 1H), 4.07 (q, J=6 Hz, 2H), 3.03 (m, 3H), 2.91(m, 3H), 2.73 (m, 1H), 2.26 (bs, 1H), 1.46 (t, J=6 Hz, 3H), 1.32 (d, J=7Hz, 3H). MS calculated for C₁₅H₁₇BrF₃NO₂+H: 380, observed: 380.

Example 8(R,S)8-Bromo-7-isopropoxy-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine

N-Trifluoroacetyl-8-bromo-7-isopropoxy-1methyl-2,3,4,5-tetrahydro-1H-3-benzazepine

A solution ofN-trifluoroacetyl-8-bromo-7-hydroxy-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine(0.035 g, 0.099 mmol) in dichloromethane (1 mL) was treated withisopropyl bromide (0.037 g, 0.297 mmol), DBU (0.048 g, 0.205 mmol) andstirred 2 hours at 20° C. The product mixture was diluted with EtOAc (10mL), washed with 5% aqueous HCl (5 mL), brine (5 mL), dried with Na₂SO₄and concentrated. Flash chromatography (15% EtOAc in hexane, silica)resulted in 0.014 g of a clear oil. MS calculated for C₁₆H₁₉BrF₃NO₂+H:394, observed: 394.

8-Bromo-7-Isopropoxy-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine

A solution ofN-trifluoroacetyl-8-bromo-7-isopropoxy-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine(0.014 g, 0.035 mmol) in methanol (1 mL) was treated with 15% aqueousNaOH (1 mL), and stirred overnight at 20° C. The product mixture wasdiluted with water (3 mL), extracted twice with EtOAc (5 mL), thecombined organic phases were washed with brine (3 mL), dried with Na₂SO₄and concentrated to give 0.008 g of a clear oil. ¹H NMR (400 MHz, CDCl₃)δ 7.24 (s, 1H), 6.64 (s, 1H), 4.48 (m, 1H), 2.98 (m, 3H), 2.87 (m, 3H),1.36 (m, 6H), 1.30 (d, J=7 Hz, 3H). MS calculated for C₁₄H₂₀BrNO+H: 298,observed: 298.

Example 9(R,S)N-Methyl-8-bromo-7-methoxy-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine

A solution of8-Bromo-7-methoxy-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine (6 mg,0.022 mmol) in methanol (1 mL) was treated with excess paraformaldehyde,1.0 M HCl in ether (0.004 mL, 0.004 mmol), NaBH₃CN (1.0 mg, 0.013 mmol),and stirred overnight at 20° C. The product mixture was diluted with 5%aqueous NaOH (5 mL), extracted 3 times with CH₂Cl₂ (5 mL each), thecombined organic phases were dried with Na₂SO₄ and concentrated. Flashchromatography (10% MeOH in CH₂Cl₂, silica) resulted in 5 mg of a clearoil. ¹H NMR (400 MHz, CDCl₃) δ 7.31 (s, 1H), 6.66 (s, 1H), 3.87 (s, 3H),3.26 (bm, 2H), 3.01 (bs, 1H), 2.85 (m, 2H), 2.45 (s, 3H), 2.45-2.25 (m,2H), 1.36 (d, J=7 Hz, 3H). MS calculated for C₁₁H₁₈BrNO+H: 284,observed: 284.

Example 10(R,S)N-Propyl-8-bromo-7-methoxy-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine

A solution of8-Bromo-7-methoxy-1-methyl-1,2,4,5-tetrahydro-3H-3-benzazepine (6 mg,0.022 mmol) in methanol (1 mL) was treated with propionaldehyde (5.0 mg,0.067 mmol), 1.0 M HCl in ether (0.004 mL, 0.004 mmol), NaBH₃CN (1.0 mg,0.013 mmol), and stirred overnight at 20° C. The product mixture wasdiluted with 5% aqueous NaOH (5 mL), extracted 3 times with CH₂Cl₂ (5 mLeach), the combined organic phases were dried with Na₂SO₄ andconcentrated. Flash chromatography (10% MeOH in CH₂Cl₂, silica) resultedin 4 mg of a clear oil. ¹H NMR (400 MHz, CD₃OD) δ 7.33 (s, 1H), 6.87 (s,1H), 3.84 (s, 3H), 3.25 (m, 2H), 3.11 (m, 2H), 2.97 (m, 1H), 2.78 (bm,2H), 2.63 (bm, 2H), 1.67 (m, 2H), 1.38 (d, J=7 Hz, 3H), 0.96 (t, J=7 Hz,3H). MS calculated for C₁₅H₂₂BrNO+H: 312, observed: 312.

Example 11(R,S)7-Hydroxy-8-iodo-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine

N-Trifluoroacetyl-7-hydroxy-8-iodo-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine

A solution ofN-trifluoroacetyl-8-iodo-7-methoxy-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine(80 mg, 0.19 mmol) in dichloromethane (3 mL) was treated with BBr₃ (0.40mL of a 1.0M solution in CH₂Cl₂, 0.40 mmol) and stirred overnight at 20°C. The excess BBr₃ was quenched with water and the product mixture wasdiluted with ether (20 mL), washed with Na₂CO₃ (10 mL) and brine (10mL), dried with Na₂SO₄ and concentrated. Flash chromatography (15% EtOAcin hexane, silica) resulted in 74 mg of a white solid. MS calculated forC₁₃H₁₃F₃INO₂+H: 400, observed: 400.

7-Hydroxy-8-iodo-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine

A solution ofN-trifluoroacetyl-7-hydroxy-8-iodo-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine(25 mg, 0.063 mmol) in methanol (2 mL) was treated with 15% aqueous NaOH(2 mL), and stirred overnight at 20° C. The product mixture was dilutedwith water (5 mL), extracted twice with EtOAc (5 mL), the combinedorganic phases were washed with brine (5 mL), dried with Na₂SO₄ andconcentrated to give 13 mg of a white solid. ¹H NMR (400 MHz, CD₃OD) δ7.46 (s, 1H), 6.64 (s, 1H), 3.16 (m, 3H), 2.94 (m, 3H), 2.81 (m, 1H),1.35 (d, J=7 Hz, 3H). MS calculated for C₁₁H₁₄INO+H: 304, observed: 304.

Example 12(R,S)7-Allyloxy-8-iodo-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine

N-Trifluoroacetyl-7-allyloxy-8-iodo-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine

A solution ofN-trifluoroacetyl-7-hydroxy-8-iodo-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine(30 mg, 0.075 mmol) in dichloromethane (2 mL) was treated with allylbromide (18 mg, 0.15 mmol), DBU (23 mg, 0.15 mmol) and stirred 2 hoursat 20° C. The product mixture was diluted with EtOAc (10 mL), washedwith 5% aqueous HCl (5 mL), brine (5 mL), dried with Na₂SO₄ andconcentrated. Flash chromatography (15% EtOAc in hexane, silica)resulted in 23 mg of a clear oil. MS calculated for C₁₆H₁₇F₃INO₂+H: 440,observed: 440.

7-Allyloxy-8-iodo-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine

A solution ofN-trifluoroacetyl-7-allyloxy-8-iodo-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine(23 mg, 0.058 mmol) in methanol (2 mL) was treated with 15% aqueous NaOH(2 mL), and stirred overnight at 20° C. The product mixture was dilutedwith water (5 mL), extracted twice with EtOAc (5 mL), the combinedorganic phases were washed with brine (5 mL), dried with Na₂SO₄ andconcentrated to give 18 mg of a white solid. MS calculated forC₁₄H₁₈NO+H: 344, observed: 344.

Example 13(R,S)3,5-Dimethyl-6,7,8,9-tetrahydro-5H-1-oxa-7-aza-cycloheptaindene

N-trifluoroacetyl-3,5-dimethyl-6,7,8,9-tetrahydro-5H-1-oxa-7-aza-cycloheptaindene

A solution ofN-trifluoroacetyl-7-allyloxy-8-iodo-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine(158 mg, 0.360 mmol) in dimethylformamide (4 mL) was treated with KOAc(106 mg, 1.08 mmol), n-Bu₄NBr (116 mg, 0.360 mmol), PPh₃ (13 mg, 0.036mmol), Pd(OAc)₂ (4 mg, 0.018 mmol) and stirred overnight at 100° C. Theproduct mixture was filtered, water (10 mL) added and then extractedtwice with EtOAc (10 mL). The combined organic phases were washed withbrine (10 mL), dried with Na₂SO₄ and concentrated. Flash chromatography(5% EtOAc in hexane, silica) resulted in 15 mg of a clear oil. MScalculated for C₁₆H₁₆F₃NO₂+H: 312, observed: 312.

3,5-Dimethyl-6,7,8,9-tetrahydro-5H-1-oxa-7-aza-cycloheptaindene

A solution ofN-trifluoroacetyl-3,5-dimethyl-6,7,8,9-tetrahydro-5H-1-oxa-7-aza-cycloheptaindenecycloheptaindene(15 mg, 0.048 mmol) in methanol (2 mL) was treated with 15% aqueous NaOH(2 mL), and stirred overnight at 20° C. The product mixture was dilutedwith water (5 mL), extracted twice with EtOAc (5 mL), the combinedorganic phases were washed with brine (5 mL), dried with Na₂SO₄ andconcentrated to give 10 mg of a white solid. ¹H NMR (400 MHz, CDCl₃) δ7.25 (s, 1H), 7.12 (s, 1H), 7.09 (s, 1H), 3.12 (m, 1H), 2.97 (m, 4H),2.85 (m, 1H), 2.64 (bm, 1H), 2.15 (s, 3H), 1.34 (d, J=8 Hz, 3H). MScalculated for C₁₄H₁₇NO+H: 216, observed: 216.

Example 14(R,S)7-Allyloxy-1-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine

N-Trifluoroacetyl-8-chloro-7-hydroxy-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine

A solution ofN-trifluoroacetyl-8-chloro-7-methoxy-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine(48 mg, 0.15 mmol) in dichloromethane (2 mL) was treated with BBr₃ (0.30mL of a 1.0M solution in CH₂Cl₂, 0.30 mmol) and stirred overnight at 20°C. The excess BBr₃ was quenched with water and the resulting mixturediluted with ether (20 mL), washed with Na₂CO₃ (10 mL) and brine (10mL), dried with Na₂SO₄ and concentrated. Flash chromatography (15% EtOAcin hexane, silica) resulted in 24 mg of a white solid. MS calculated forC₁₃H₁₃CIF₃NO₂+H: 308, observed: 308.

N-Trifluoroacetyl-7-allyloxy-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine

A solution ofN-trifluoroacetyl-8-chloro-7-hydroxy-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine(24 mg, 0.078 mmol) in dichloromethane (2 mL) was treated with allylbromide (18 mg, 0.15 mmol), DBU (23 mg, 0.15 mmol) and stirred 2 hoursat 20° C. The product mixture was diluted with EtOAc (10 mL), washedwith 5% aqueous HCl (5 mL), brine (5 mL), dried with Na₂SO₄ andconcentrated. Flash chromatography (15% EtOAc in hexane, silica)resulted in 23 mg of a white solid. MS calculated for C₁₆H₁₇CIF₃NO₂+H:348, observed: 348.

7-Allyloxy-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine

A solution ofN-trifluoroacetyl-7-allyloxy-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine(23 mg, 0.066 mmol) in methanol (2 mL) was treated with 15% aqueous NaOH(2 mL), and stirred overnight at 20° C. The product mixture was dilutedwith water (5 mL), extracted twice with EtOAc (5 mL), the combinedorganic phases were washed with brine (5 mL), dried with Na₂SO₄ andconcentrated to give 19 mg of a white solid. ¹H NMR (400 MHz, CD₃OD) δ7.12 (s, 1H), 6.81 (s, 1H), 6.03 (m, 1H), 5.43 (d, J=17 Hz, 1H), 5.24(d, J=10 Hz, 1H), 4.57 (d, J=5 Hz, 2H), 3.1-2.9 (m, 5H), 2.81 (m, 1H),2.63 (m, 1H), 1.30 (d, J=7 Hz, 3H).

Example 15(R,S)7-Methoxy-1-methyl-8-(2-thienyl)-2,3,4,5-tetrahydro-1H-3-benzazepine

N-Trifluoroacetyl-7-methoxy-1-methyl-(2-thienyl)-2,3,4,5-tetrahydro-1H-3-benzazepine

A solution ofN-trifluoromethylacetyl-8-bromo-7-methoxy-1-methyl-1,2,4,5-tetrahydro-3H-3-benzazepine(51 mg, 0.14 mmol) in 1,4-dioxane (2 mL) was treated withthiophene-2-boronic acid (36 mg, 0.28 mmol), K₂CO₃ (58 mg, 0.42 mmol),water (0.1 mL), Pd(PPh₃)₄ (16 mg, 0.014 mmol) and stirred overnight at100° C. The product mixture was diluted with EtOAc, filtered, absorbedon silica and purified by flash chromatograghy (10% EtOAc in hexane,silica) resulting in 28 mg of a yellow solid. MS calculated forC₁₈H₁₈F₃NO₂S+H: 370, observed: 370.

7-Methoxy-1-methyl-8-(2-thienyl)-2,3,4,5-tetrahydro-1H-3-benzazepine

A solution ofN-trifluoroacetyl-7-methoxy-1-methyl-8-(2-thienyl)-2,3,4,5-tetrahydro-1H-3-benzazepine(28 mg, 0.076 mmol) in methanol (2 mL) was treated with 15% aqueous NaOH(2 mL), and stirred 0.5 hours at 50° C. The product mixture was dilutedwith water (5 mL), extracted twice with EtOAc (5 mL), the combinedorganic phases were washed with brine (5 mL), dried with Na₂SO₄ andconcentrated to give 18 mg of a yellow oil. ¹H NMR (400 MHz, CDCl₃) δ7.45 (d, J=4 Hz, 1H), 7.39 (s, 1H), 7.27 (d, J=6 Hz, 1H), 7.07 (dd, J=4,6 Hz, 1H), 6.71 (s, 1H), 3.90 (s, 3H), 3.1-2.9 (m, 6H), 2.80 (m, 1H),2.22 (bs, 1H), 1.38 (d, J=7 Hz, 3H). MS calculated for C₁₆H₁₉NOS+H: 274,observed: 274.

Example 16(R,S)8-Cyano-7-methoxy-1-methyl-3,4,5-tetrahydro-1H-3-benzazepine

N-Trifluoroacetyl-8-cyano-7-methoxy-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine

A solution ofN-trifluoroacetyl-8-bromo-7-methoxy-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine(18 mg, 0.05 mmol) in dimethylformamide (1 mL) was treated with CuCN (20mg, 0.24 mmol) and the mixture was microwaved at 200° C. for 0.5 hours.The product mixture was diluted with water (5 mL), extracted twice withEtOAc (5 mL), the combined organic phases were washed with brine (5 mL),dried with Na₂SO₄ and concentrated. Flash chromatography (35% EtOAc inhexane, silica) resulted in 10 mg of a clear oil. MS calculated forC₁₅H₁₅F₃N₂O₂+H: 313, observed: 313.

8-Cyano-7-methoxy-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine

A solution ofN-trifluoroacetyl-8-cyano-7-methoxy-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine(10 mg, 0.032 mmol) in methanol (2 ml) was treated with 15% aqueous NaOH(2 mL), and stirred 1 hour at 50° C. The product mixture was dilutedwith water (5 mL), extracted twice with EtOAc (5 mL), the combinedorganic phases were washed with brine (5 mL), dried with Na₂SO₄ andconcentrated to give 6.0 mg of a white solid. ¹H NMR (400 MHz, CD₃OD) δ7.33 (s, 1H), 6.93 (s, 1H), 3.91 (s, 3H), 3.18-2.97 (m, 5H), 2.80 (m,1H), 2.60 (m, 1H), 1.33 (d, J=8 Hz, 3H). MS calculated for C₁₃H₁₆N₂O+H:217, observed: 217.

Example 17(R,S)8-bromo-1-cyclopropyl-7-methoxy-2,3,4,5-tetrahydro-1H-3-benzazepine

N-Trifluoroacetyl-1-cyclopropyl-7-methoxy-2,3,4,5-tetrahydro-1H-3-benzazepine

A solution of diethyl zinc (1 mL, 1 M in hexanes) in dichloromethane (1mL) at 0° C. was treated with trifluoroacetic acid in dichloromethane(0.5 mL) and the mixture stirred for 15 min. Diiodomethane (0.280 g, 1.0mmol) in dichloromethane (0.5 mL) was then added and stirred for 15minutes.N-Trifluoroacetyl-7-methoxy-1-methylene-2,3,4,5-tetrahydro-1H-3-benzazepine(0.075 g, 0.26 mmol) in dichloromethane (1 mL) was added and the mixturestirred for 30 minutes at 0° C. and then for 2 hours at 20° C. Theproduct mixture was quenched with aqueous saturated NH₄Cl (5 mL),extracted twice with CH₂Cl₂ (20 mL), washed with saturated aqueousNaHCO₃ (10 mL), washed with H₂O (10 mL), and concentrated. Flashchromatography (7% EtOAc in hexanes, silica) resulted in 0.050 g of awhite solid. MS calculated for C₁₅H₁₆F₃NO₂+H: 300, observed: 300.

N-Trifluoroacetyl-8-bromo-1-cyclopropyl-7-methoxy-2,3,4,5-tetrahydro-1H-3-benzazepine

A solution ofN-trifluoroacetyl-1-cyclopropyl-7-methoxy-2,3,4,5-tetrahydro-1H-3-benzazepine(0.025 g, 0.08 mmol) in acetonitrile (1 mL) was treated withN-bromosuccinimide (0.032 g, 0.18 mmol) and stirred for 2 hrs. at 50° C.The product mixture was concentrated and then purified by flashchromatography (10% EtOAc in hexanes, silica) resulting in 0.014 g of awhite solid. MS calculated for C₁₅H₁₅BrF₃NO₂+H: 378, observed: 378.

8-bromo-1-cyclopropyl-7-methoxy-2,3,4,5-tetrahydro-1H-3-benzazepine

A solution ofN-trifluoroacetyl-8-bromo-1-cyclopropyl-7-methoxy-2,34,5-tetrahydro-1H-3-benzazepine(0.014 g, 0.037 mmol) in methanol (1 mL) was treated with 15% aqueousNaOH (1 mL), and stirred for 2 hours at 50° C. The product mixture wasdiluted with brine (10 mL), extracted twice with EtOAc (10 mL), driedwith MgSO₄, and concentrated to give 0.008 g of a clear oil. ¹H NMR (400MHz, CD₃OD) δ 7.26 (s, 1H), 6.78 (s, 1H), 3.83 (s, 3H), 3.02 (m, 2H),2.92 (m, 2H), 2.67 (s, 2H), 0.91 (m, 2H), 0.85 (m, 2H). MS calculatedfor C₁₃H₁₆BrNO+H: 282, observed: 282.

Example 18(R,S)8-bromo-1-hydroxymethyl-7-methoxy-2,3,4,5-tetrahydro-1H-3-benzazepine

N-Trifluoroacetyl-1-hydroxymethyl-7-methoxy-2,3,4,5-tetrahydro-1H-3-benzazepine

A solution ofN-trifluoroacetyl-7-methoxy-1-methylene-2,3,4,5-tetrahydro-1H-3-benzazepine(0.100 g, 0.35 mmol) in tetrahydrofuran (1 mL) was treated with BH₃-THFcomplex (0.36 mL, 1 M in THF), and stirred for 30 min. at 20° C. Water(0.5 mL), saturated aqueous NaHCO₃ (0.5 mL), and 30% H₂O₂ (0.2 mL) wereadded sequentially and the reaction stirred for 30 min. at 20° C. Theproduct mixture was diluted with EtOAc (10 mL), washed with brine (10mL), and concentrated. Flash chromatography (33% EtOAc in hexane,silica) resulted in 0.035 g of a clear oil. MS calculated forC₁₄H₁₆F₃NO₃+H: 304, observed: 304.

N-Trifluoroacetyl-8-bromo-1-hydroxymethyl-7-methoxy-2,3,4,5-tetrahydro-1H-3-benzazepine

A solution ofN-trifluoromethylacetyl-1-hydroxymethyl-7-methoxy-2,3,4,5-tetrahydro-1H-3-benzazepine(0.035 g, 0.12 mmol) in acetonitrile (1 mL) was treated withN-bromosuccinimide (0.025 g, 0.14 mmol), and stirred for 30 min. at 20°C. The product mixture was concentrated and then purified by flashchromatography (33% EtOAc in hexane, silica) resulting in 0.019 g clearoil. MS calculated for C₁₄H₁₅BrF₃NO₃+H: 382, observed: 382.

8-bromo-1-hydroxymethyl-7-methoxy-2,3,4,5-tetrahydro-1H-3-benzazepine

A solution ofN-trifluoroacetyl-8-bromo-1-hydroxymethyl-7-methoxy-2,3,4,5-tetrahydro-1H-3-benzazepine(0.009 g, 0.024 mmol) in methanol (1 mL) was treated with 15% aqueousNaOH (1 mL), and stirred for 1 hour at 50° C. The product mixture wasdiluted with brine (5 mL), extracted twice with EtOAc (5 mL), dried withMgSO₄, and concentrated to give 0.006 g clear oil. ¹H NMR (400 MHz,CD₃OD) δ 7.28 (s, 1H), 6.79 (s, 1H), 3.84 (m, 2H), 3.0-2.8 (m, 7H). MScalculated for C₁₂H₁₆BrNO₂+H: 286, observed: 286.

Example 19(R,S)8-Bromo-1-ethyl-7-methoxy-2,3,4,5-tetrahydro-1H-3-benzazepine

N-Crotyl, N-trifluoroacetyl-2-iodo-5-methoxyphenethylamine

A solution of N-trifluoroacetyl-2-iodo-5-methoxyphenethylamine (6.68 g,17.9 mmol) in toluene (100 mL) was treated with K₂CO₃ (3.22 g, 23.3mmol), KOH (3.01 g, 53.7 mmol), n-Bu₄NBr (0.580 g, 1.80 mmol) and crotylbromide (3.15 g, 23.3 mmol). The mixture was stirred at 75° C. for 16hours, cooled to 20° C., diluted with Et₂O (500 mL), washed with 10%aqueous HCl (500 mL) and concentrated. Flash chromatography (10% EtOAcin hexane, silica) resulted in 5.22 g of a clear oil. MS calculated forC₁₅H₁₇F₃INO₂+H: 428, observed: 428.

N-Trifluoroacetyl-1-ethylene-7-methoxy-2,3,4,5-tetrahydro-1H-3-benzazepine

A solution of N-crotyl, N-trifluoroacetyl-2-iodo-5-methoxyphenethylamine(5.20 g, 12.2 mmol) in dimethylformamide (80 mL) was treated with KOAc(3.59 g, 36.6 mmol), n-Bu₄NBr (3.93 g, 12.2 mmol), PPh₃ (0.320 g, 1.22mmol), Pd(OAc)₂ (0.137 g, 0.61 mmol) and stirred overnight at 90° C. Theproduct mixture was cooled to 20° C., diluted with water (200 mL),extracted twice with ether (500 mL), the combined organic phases washedtwice with brine (200 mL), and concentrated. Flash chromatography (10%EtOAc in hexane, silica) resulted in 2.29 g of a clear oil, whichconsists of a mixture of olefinic isomers. MS calculated forC₁₅H₁₆F₃NO₂+H: 300, observed: 300.

N-Trifluoroacetyl-1-ethyl-7-methoxy-2,3,4,5-tetrahydro-1H-3-benzazepine

A solution ofN-trifluoroacetyl-1-ethylene-7-methoxy-2,3,4,5-tetrahydro-1H-3-benzazepine(2.29 g, 7.65 mmol) in methanol (100 mL) was treated with 10% Pd/C (4.0g, 0.77 mmol)) and stirred overnight under an atmosphere of hydrogen.The product mixture was filtered through a pad of celite and silica, andthe solvent removed to give 2.14 g of a clear oil. MS calculated forC₁₅H₁₈F₃NO₂+H: 302, observed 302.

N-Trifluoroacetyl-8-bromo-1-ethyl-7-methoxy-2,3,4,5-tetrahydro-1H-3-benzazepine

A solution ofN-trifluorolacetyl-1-ethyl-7-methoxy-2,3,4,5-tetrahydro-1H-3-benzazepine(0.710 g, 2.36 mmol) in acetonitrile (20 mL) was treated withN-bromosuccinimide (0.504 g, 2.83 mmol), and stirred overnight at 20° C.The product mixture was concentrated, diluted with EtOAc (100 mL),washed with water (50 mL) and brine (50 mL), dried with Na₂SO₄ andconcentrated. Flash chromatography (10% EtOAc in hexanes, silica)resulted in 0.561 g of a clear oil. MS calculated for C₁₅H₁₇BrF₃NO₂+H:380, observed: 380.

8-Bromo-1-ethyl-7-methoxy-2,3,4,5-tetrahydro-1H-3-benzazepine

A solution ofN-trifluoroacetyl-8-bromo-1-ethyl-7-methoxy-2,3,4,5-tetrahydro-1H-3-benzazepine(0.561 g, 1.48 mmol) in methanol (30 mL) was treated with 15% aqueousNaOH (30 mL), and stirred overnight at 20° C. The product mixture wasdiluted with brine (100 mL), extracted twice with EtOAc (200 mL), driedwith MgSO₄, and concentrated to give 0.412 g of a clear oil. ¹H NMR (400MHz, CD₃OD) δ 7.24 (s, 1H), 6.76 (s, 1H), 3.83 (s, 3H), 3.02 (m, 3H),2.91 (s, 1H), 2.85-2.76 (m, 3H), 2.63 (m, 1H), 1.78 (m, 1H), 1.72 (m,1H), 0.94 (dd, J=8, 8 Hz, 3H). MS calculated for C₁₃H₁₈BrNO+H: 284,observed: 284.

Example 20(R,S)8-Chloro-1-ethyl-7-methoxy-2,3,4,5-tetrahydro-1H-3-benzazepine

N-Trifluoroacetyl-8-chloro-1-ethyl-7-methoxy-2,3,4,5-tetrahydro-1H-3-benzazepine

A solution ofN-trifluorolacetyl-1-ethyl-7-methoxy-2,3,4,5-tetrahydro-1H-3-benzazepine(0.600 g, 1.99 mmol) in acetonitrile (20 mL) was treated withN-chlorosuccinimide (0.057 g, 0.32 mmol), and stirred overnight at 60°C. The product mixture was concentrated, diluted with EtOAc (100 mL),washed with water (50 mL) and brine (50 mL), dried with Na₂SO₄ andconcentrated. Flash chromatography (10% EtOAc in hexanes, silica)resulted in 0.421 g of a clear oil. MS calculated for C₁₅H₁₇CIF₃NO₂H:336, observed: 336.

8-Chloro-1-ethyl-7-methoxy-2,3,4,5-tetrahydro-1H-3-benzazepine

A solution ofN-trifluoroacetyl-8-chloro-1-ethyl-7-methoxy-2,3,4,5-tetrahydro-1H-3-benzazepine(0.421 g, 1.25 mmol) in methanol (30 mL) was treated with 15% aqueousNaOH (30 mL), and stirred overnight at 20° C. The product mixture wasdiluted with brine (100 mL), extracted twice with EtOAc (200 mL), driedwith MgSO₄, and concentrated to give 0.241 g of a clear oil. ¹H NMR (400MHz, CD₃OD) δ 7.05 (s, 1H), 6.79 (s, 1H), 3.84 (s, 3H), 3.03 (m, 3H),2.91 (s, 1H), 2.86-2.76 (m, 3H), 2.64 (m, 1H), 1.81 (m, 1H), 1.72 (m,1H), 0.93 (dd, J=8, 8 Hz, 3H). MS calculated for C₁₃H₁₈ClNO+H: 240,observed: 240.

Example 21(R,S)8-Bromo-1-isopropyl-7-methoxy-2,3,4,5-tetrahydro-1H-3-benzazepine

N-(3-methylbut-2-enyl), N-trifluoroacetyl-2-iodo-5-methoxyphenethylamine

A solution of N-trifluoroacetyl-2-iodo-5-methoxyphenethylamine (0.700 g,1.88 mmol) in toluene (25 mL) was treated with K₂CO₃ (0.340 g, 2.4mmol), KOH (0.210 g, 3.76 mmol), n-Bu₄NBr (0.060 g, 0.19 mmol) and4-bromo-2-methyl-2-butene (0.364 g, 2.44 mmol). The mixture was stirredat 80° C. for 3 hours, cooled to 20° C., diluted with ether (100 mL),washed with 10% HCl (50 mL) and concentrated. Flash chromatography (10%EtOAc in hexane, silica) resulted in 0.272 g of a clear oil. ¹H NMR (400MHz, CDCl₃, mixture of rotamers) δ 7.65 (m, 1H), 6.75 (m, 1H), 6.54 (m,1H), 5.20 (m, 4H), 5.0 (m, 6H), 4.10 (m, 1H), 3.82 (m, 1H), 3.76 (d,2H), 3.50 (m, 2H), 3.02 (m, 2H), 1.75 (m, 3H), 1.66 (m, 3H).

N-Trifluoroacetyl-1-isopropylene-7-methoxy-2,3,4,5-tetrahydro-1H-3-benzazepine

A solution of N-(3-methylbut-2-enyl),N-trifluoroacetyl-2-iodo-5-methoxyphenethylamine (0.0272 g, 0.62 mmol)in dimethylformamide (12 mL) was treated with KOAc (0.183 g, 1.86 mmol),n-Bu₄NBr (0.200 g, 0.062 mmol), PPh₃ (0.016 g, 0.062 mmol), Pd(OAc)₂(0.183 g, 1.86 mmol) and stirred overnight at 90° C. The product mixturewas cooled to 20° C., diluted with water (50 mL), extracted twice withether (50 mL), the combined organic phases were washed with brine (50mL), and concentrated. Flash chromatography (10% EtOAc in hexane,silica) resulted in 0.096 g of a clear oil. MS calculated forC₁₆H₁₈F₃NO₂+H: 314, observed: 314.

N-Trifluoroacetyl-1-isopropyl-7-methoxy-2,3,4,5-tetrahydro-1H-3-benzazepine

A solution ofN-trifluoroacetyl-1-isopropylene-7-methoxy-2,3,4,5-tetrahydro-1H-3-benzazepine(0.096 g, 0.31 mmol) in ethanol (2 mL) was treated with 10% Pd/C (0.033g, 0.031 mmol)) and stirred overnight under an atmosphere of hydrogen.The product mixture was filtered through a pad of celite and silica, andthe solvent removed to give 0.091 g of a clear oil. MS calculated forC₁₆H₂F₃NO₂+H: 316, observed: 316.

N-Trifluoroacetyl-8-bromo-1-isopropyl-7-methoxy-2,3,4,5-tetrahydro-1H-3-benzazepine

A solution ofN-trifluorolacetyl-1-isopropyl-7-methoxy-2,3,4,5-tetrahydro-1H-3-benzazepine(0.091 g, 0.29 mmol) in acetonitrile (3 mL) was treated withN-bromosuccinimide (0.057 g, 0.32 mmol), and stirred overnight at 20° C.After removing the solvent, flash chromatography (10% EtOAc in hexanes,silica) resulted in 0.056 g of a clear oil. MS calculated forC₁₆H₁₉BrF₃NO₂+H: 394, observed: 394.

8-Bromo-1-isopropyl-7-methoxy-2,3,4,5-tetrahydro-1H-3-benzazepine

A solution ofN-trifluoroacetyl-8-bromo-1-isopropyl-7-methoxy-2,3,4,5-tetrahydro-1H-3-benzazepine(0.013 g, 0.03 mmol) methanol (0.5 mL) was treated with 15% aqueous NaOH(0.5 mL), and stirred overnight at 20° C. The product mixture wasdiluted with brine (5 mL), extracted twice with EtOAc (5 mL), dried withMgSO₄, and concentrated to give 0.10 g of a clear oil. ¹H NMR (400 MHz,CD₃OD) δ 7.08 (s, 1H), 6.64 (s, 1H), 3.72 (s, 3H), 3.2-3.10 (m, 3H),2.7-2.5 (m, 3H), 2.3-2.1 (m, 2H), 0.96 (d, 3H), 0.63 (d, 3H). MScalculated for C₁₄H₂₀BrNO+H: 298, observed: 298.

Example 22(R,S)8-Bromo-7-hydroxy-1-isopropyl-2,3,4,5-tetrahydro-1H-3-benzazepine

N-Trifluoroacetyl-8-bromo-7-hydroxy-1-isopropyl-2,3,4,5-tetrahydro-1H-3-benzazepine

A solution ofN-trifluoroacetyl-8-bromo-1-isopropyl-7-methoxy-2,3,4,5-tetrahydro-1H-3-benzazepine(0.041 g, 0.10 mmol) in dichloromethane (1 mL) was treated with BBr₃(0.32 ml, 1.0 M solution in CH₂Cl₂) and stirred overnight at 20° C. Theexcess BBr₃ is quenched with water and the resulting mixture dilutedwith ether (50 mL), washed twice with saturated aqueous Na₂CO₃ (20 mL)and concentrated. Flash chromatography (20% EtOAc in hexanes, silica)resulted in 0.037 g clear oil. MS calculated for C₁₅H₁₇BrF₃NO₂+H: 380,observed: 380.

8-Bromo-7-hydroxy-1-isopropyl-2,3,4,5-tetrahydro-1H-3-benzazepine

A solution ofN-trifluoroacetyl-8-bromo-7-hydroxy-1-isopropyl-2,3,4,5-tetrahydro-1H-3-benzazepine(0.018 g, 0.047 mmol) in methanol (1 mL) was treated with 15% aqueousNaOH (1 mL), and stirred for 3 hours at 50° C. The product mixture wasbrought to pH 7-8 with 10% aqueous HCl, extracted three times with EtOAc(50 mL), dried with MgSO₄, and concentrated to give 0.013 g of a whitesolid. ¹H NMR (400 MHz, CD₃OD) δ 7.10 (s, 1H), 6.60 (s, 1H), 3.30 (m,1H), 3.2-3.0 (m, 2H), 2.78 (m, 1H), 2.7-2.5 (m, 2H), 2.3-2.1 (m, 2H),1.05 (d, 3H), 0.73 (d, 3H). MS calculated for C₁₃H₁₈BrNO+H: 284,observed: 284.

Example 23(R,S)7-Allyloxy-8-bromo-1-isopropyl-2,3,4,5-tetrahydro-1H-3-benzazepine

N-Trifluoroacetyl-7-allyloxy-8-bromo-1-isopropyl-2,3,4,5-tetrahydro-1H-3-benzazepine

A solution ofN-trifluoroacetyl-8-bromo-7-hydroxy-1-isopropyl-2,3,4,5-tetrahydro-1H-3-benzazepine(0.017 g, 0.045 mmol) in dichloromethane (1 mL) was treated withN′″-tert-butyl-N,N,N′,N′,N″,N″-hexamethylphosphorimidic triamide (0.016g, 0.068 mmol), allyl bromide (0.011 g, 0.09 mmol) and stirred for 3hours at 20° C. The product mixture was diluted with 10% aqueous HCl,extracted twice with dichloromethane (20 mL), and concentrated. Flashchromatography (10% EtOAc in hexanes, silica) resulted in 0.011 g of aclear oil. MS calculated for C₁₈H₂₁BrF₃NO₂+H: 420, observed: 420.

7-Allyloxy-8-bromo-1-isopropyl-2,3,4,5-tetrahydro-1H-3-benzazepine

A solution ofN-trifluoroacetyl-7-allyloxy-8-bromo-1-isopropyl-2,3,4,5-tetrahydro-1H-3-benzazepine(0.011 g, 0.026 mmol) in methanol (0.5 mL) was treated with of 15%aqueous NaOH (0.5 mL), and stirred for 3 hours at 50° C. The productmixture was diluted with brine (5 mL), extracted twice with EtOAc (5mL), dried with MgSO₄, and concentrated to give 0.010 g of a clear oil.¹H NMR (400 MHz, CD₃OD) δ 7.09 (s, 1H), 6.62 (s, 1H), 5.94 (m, 1H), 5.32(dd, 1H), 5.12 (dd, 1H), 4.46 (d, 2H), 3.19 (m, 1H), 3.05 (m, 2H), 2.66(m, 1H), 2.5 (bm, 2H), 2.3-2.1 (m, 2H), 0.95 (d, 3H), 0.63 (d, 3H). MScalculated for C₁₆H₂₂BrNO+H: 324, observed: 324.

Example 248-Bromo-7-methoxy-1,4-dimethyl-2,3,4,5-tetrahydro-1H-3-benzazepine

N-Trifluoroacetyl-1-(3-methoxyphenyl)-2-propylamine

A solution of 1-(3-methoxyphenyl)-2-propylamine (3.59 g, 21.7 mmol) indichloromethane (75 mL) at 0° C., was treated with pyridine (2.1 mL,28.2 mmol), trifluoracetic anhydride (5.9 g, 28.2 mmol), and thenstirred for 3 hours while warming to 20° C. The product mixture wasdiluted with EtOAc (300 mL), washed sequentially with 10% aqueous HCl(100 mL), water (100 mL), brine (100 mL), dried with Na₂SO, andconcentrated. Flash chromatography (20% EtOAc in hexane, silica)resulted in 4.29 g of a yellow solid. ¹H NMR (400 MHz, CD₃OD) δ 7.17(dd, J=8, 8 Hz, 1H), 6.76 (m, 3H), 4.19 (m, 1H), 3.77 (s, 3H), 2.78 (m,2H), 1.21 (d, J=7 Hz, 2H).

N-Trifluoroacetyl-1-(2-iodo-5-methoxyphenyl)-2-propylamine

A solution of N-trifluoroacetyl-1-(3-methoxyphenyl)-2-propylamine (4.29g, 15.7 mmol) in methanol (100 mL) was cooled to −78° C. and treatedwith CaCO₃ (3.17 g, 31.4 mmol), followed by a solution of ICl (6.37 g,39.3 mmol) in methanol (50 mL). The reaction was allowed to warm to 20°C. while stirring overnight. The product mixture was filtered,concentrated, dissolved in EtOAc (200 mL), washed twice with 5% aqueoussodium bisulfite (100 mL), once with brine (100 mL), dried with Na₂SO₄and concentrated to give 6.72 g of a white solid powder. MS calculatedfor C₁₂H₁₃F₃INO₂+H: 388, observed: 388.

N-Allyl, N-trifluoroacetyl-1-(2-iodo-5-methoxyphenyl)-2-propylamine

A solution of N-trifluoroacetyl-1-(2-iodo-5-methoxyphenyl)-2-propylamine(6.09 g, 15.7 mmol) in toluene (450 mL) was treated with K₂CO₃ (2.82 g,20.4 mmol). KOH (2.45 g, 47.1 mmol), n-Bu₄NBr (0.506 g, 1.57 mmol) andallyl bromide (2.47 g, 20.4 mmol), and stirred overnight at 80° C. Theproduct mixture was acidified with 10% aqueous HCl, separated, theaqueous phase extracted with ether (500 mL), the combined organic phaseswere washed with brine (200 mL), dried with Na₂SO₄ and concentrated togive 4.45 g of a brown oil.

N-Trifluoroacetyl-7-methoxy-4-methyl-1-methylene-2,3,4,5-tetrahydro-1H-3-benzazepine

A solution of N-allyl,N-trifluoroacetyl-1-(2-iodo-5-methoxyphenyl)-2-propylamine (4.45 g, 10.8mmol) in dimethylformamide (120 mL) was treated with KOAc (3.17 g, 32.3mmol), n-Bu₄NBr (3.47 g, 10.8 mmol), PPh₃ (0.283 g, 1.08 mmol), Pd(OAc)₂(0.242 g, 1.08 mmol) and stirred overnight at 80° C. The product mixturewas cooled to 20° C., filtered, diluted with water (200 mL), extractedwith ether (3×200 mL), the combined organic phases washed with water(100 mL), brine (100 mL), dried with Na₂SO₄ and concentrated. Flashchromatography (10% EtOAc in hexane, silica) resulted in 1.39 g of ayellow oil.

N-Trifluoroacetyl-1,4-dimethyl-7-methoxy-2,3,4,5-tetrahydro-1H-3-benzazepine

A solution ofN-trifluoroacetyl-7-methoxy-4-methyl-1-methylene-2,3,4,5-tetrahydro-1H-3-benzazepine(1.39 g, 4.64 mmol) in ethanol (40 mL) was treated with 10% Pd/C (0.49g, 0.46 mmol) and stirred overnight under an atmosphere of hydrogen. Theproduct mixture was filtered through a pad of celite and silica and thenconcentrated. Flash chromatography (20% EtOAc in hexane, silica)resulted in 0.77 g of a clear oil. ¹H NMR (400 MHz, CDCl₃, mixture ofrotamers) δ 7.06 (m, 1H), 6.71 (m, 1H), 6.63 (m, 1H), 4.38 (bm, 1H), 3.8(s, 3H), 3.6 (m, 1H), 3.25 (m, 1H), 3.18 (bm, 2H), 2.72 (m, 1H), 1.34(m, 3H) 1.22 (m, 3H).

N-Trifluoroacetyl-8-bromo-1,4-dimethyl-7-methoxy-2,3,4,5-tetrahydro-1H-3-benzazepine

A solutionN-trifluoroacetyl-1,4-dimethyl-7-methoxy-2,3,4,5-tetrahydro-1H-3-benzazepine(0.452 g, 1.50 mmol) in acetonitrile (20 mL) was treated withN-bromosuccinimide (0.294 g, 1.65 mmol) and stirred overnight at 20° C.The product mixture was diluted with EtOAc (100 mL), washed with sodiumbisulfite (50 mL) and brine (50 mL), dried with Na₂SO₄ and concentrated.Flash chromatography (20% EtOAc in hexane, silica) resulted in a clearoil. ¹H NMR (400 MHz, CDCl₃, mixture of rotamers) δ 7.32 (s, 1H), 6.62(m, 1H), 4.37 (m, 1H), 3.87 (s, 3H), 3.81 (m, 1H), 3.28-3.10 (m, 3H),2.73 (m, 1H), 1.31 (m, 3H), 1.25 (m, 3H).

8-Bromo-1,4-dimethyl-7-methoxy-2,3,4,5-tetrahydro-1H-3-benzazepine

A solution ofN-trifluoroacetyl-8-bromo-1,4-dimethyl-7-methoxy-2,3,4,5-tetrahydro-1H-3-benzazepine(21 mg, 0.055 mmol) in methanol (2 mL) was treated with 15% aqueous NaOH(2 mL), and stirred overnight at 20° C. The product mixture was dilutedwith water (5 mL), extracted twice with EtOAc (10 mL), the combinedorganic phases were washed with brine (10 mL), dried with Na₂SO₄ andconcentrated to give 11 mg of a clear oil. ¹H NMR (400 MHz, CDCl₃) δ7.29 (s, 1H), 6.64 (s, 1H), 3.88 (s, 3H), 3.02 (m, 2H), 2.89 (dd, J=9,14 Hz, 1H), 2.80 (m, 1H), 2.67 (d, J=14 Hz, 1H), 2.53 (dd, J=10, 13, 1H)1.30 (d, J=7 Hz, 3H), 1.19 (d, J=6 Hz, 3H). MS calculated forC₁₃H₁₈BrNO+H: 284, observed: 284.

Example 257-Allyloxy-8-bromo-1,4-dimethyl-2,3,4,5-tetrahydro-1H-3-benzazepine

N-Trifluoroacetyl-8-bromo-1,4-dimethyl-7-hydroxy-2,3,4,5-tetrahydro-1H-3-benzazepine

A solution ofN-trifluoroacetyl-8-bromo-1,4-dimethyl-7-methoxy-2,3,4,5-tetrahydro-1H-3-benzazepine(0.383 g, 1.01 mmol) in dichloromethane (30 mL) was treated with BBr₃(2.35 mL of a 1.0M solution in CH₂Cl₂, 2.35 mmol) and stirred overnightwhile warming to 20° C. The excess BBr₃ is quenched with water, and theresulting mixture was diluted with ether (100 mL), washed with saturatedaqueous Na₂CO₃ (50 mL) and brine (50 mL), dried with Na₂SO₄ andconcentrated. Flash chromatography (15% EtOAc in hexane, silica)resulted in 0.302 g of a white solid. ¹H NMR (400 MHz, CDCl₃, mixture ofrotamers) δ 7.22 (m, 1H), 6.77 (m, 1H), 5.34 (s, 1H), 4.35 (m, 1H), 3.62(m, 1H), 3.24 (m, 1H), 3.13 (m, 2H), 2.69 (m, 1H), 1.31 (m, 3H), 1.22(m, 3H).

N-Trifluoroacetyl-7-allyloxy-8-bromo-1,4-dimethyl-2,3,4,5-tetrahydro-1H-3-benzazepine

A solutionN-trifluoroacetyl-8-bromo-1,4-dimethyl-7-hydroxy-2,3,4,5-tetrahydro-1H-3-benzazepine(0.030 g, 0.082 mmol) in dichloromethane (2 mL) was treated with allylbromide (0.030 g, 0.246 mmol), DBU (0.037 g, 0.246 mmol) and stirred 2hours at 20° C. The product mixture was diluted with EtOAc (10 mL),washed with 5% aqueous HCl (2 mL), brine (5 mL), dried with Na₂SO₄ andconcentrated. Flash chromatography (15% EtOAc in hexane, silica)resulted In 0.028 g of a clear dl. ¹H NMR (400 MHz, CDCl₃, mixture ofrotamers) δ 7.32 (s, 1H), 6.62 (m, 1H), 6.02 (m, 1H), 5.45 (d, J=17 Hz,1H), 5.30 (d, J=1 Hz, 1H), 4.58 (s, 2H), 4.36 (m, 1H), 3.62 (m, 1H),3.23 (m, 1H), 3.11 (m, 1H), 2.81 (d, J=10 Hz, 1H), 2.70 (m, 1H), 1.34(m, 3H), 1.21 (m, 3H).

7-Allyloxy-8-bromo-1,4-dimethyl-2,3,4,5-tetrahydro-1H-3-benzazepine

A solution ofN-trifluoroacetyl-7-allyloxy-8-bromo-1,4-dimethyl-2,3,4,5-tetrahydro-1H-3-benzazepine(0.028 g, 0.069 mmol) in methanol (2 mL) was treated with 15% aqueousNaOH (2 mL), and stirred for 3 hours at 20° C. The product mixture wasdiluted with water (10 mL), extracted twice with EtOAc (10 mL), thecombined organic phases were washed with brine (10 mL), dried withNa₂SO₄ and concentrated to give 0.020 g of a clear oil. ¹H NMR (400 MHz,CDCl₃) δ 7.30 (s, 1H), 6.64 (s, 1H), 6.06 (m, 1H), 5.47 (d, J=17 Hz,1H), 5.30 (d, J=11 Hz, 1H), 4.56 (s, 2H), 3.03 (m, 2H), 2.90 (dd, J=9,14 Hz, 1H), 2.80 (m, 1H), 2.65 (d, J=14 Hz, 1H), 2.55 (dd, J=10, 14 Hz,1H), 1.77 (bs, 1H), 1.30 (d, J=7 Hz, 3H), 1.20 (d, J=6 Hz, 3H).

Example 26 (R,S)8-Chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine

N-Trifluoroacetyl-4-chlorophenethylamine

A solution of 4-chlorophenethylamine (1.0 g, 6.4 mmol) indichloromethane (20 mL) was cooled to 0° C., treated with pyridine (1.0mL, 12.8 mmol), trifluoracetic anhydride (1.6 g, 7.7 mmol) and thenstirred for 1 hour while warming to 20° C. The product mixture wasdiluted with EtOAc (100 mL), washed sequentially with 10% aqueous HCl(50 mL), water (50 mL), brine (50 mL), dried with Na₂SO₄ andconcentrated to give 1.6 g of a white solid.

N-Trifluoroacetyl-2-iodo-4-chlorophenethylamine

A solution of N-trifluoroacetyl-4-chlorophenethylamine (1.6 g, 6.4 mmol)in dichloromethane (20 mL) was treated withbis(pyridine)iodonium(I)tetrafluoroborate (2.6 g, 7.0 mmol), CF₃SO₃H(2.1 g, 14.1 mmol) and stirred overnight at 20° C. The product mixturewas concentrated, dissolved in EtOAc (100 mL), washed twice with 5%aqueous sodium bisulfite (50 mL), twice with saturated aqueous NaHCO₃,(50 mL) once with brine (50 mL), dried with Na₂SO₄ and concentrated togive 0.94 g of a clear oil. MS calculated for C₁₀H₈CIF₃INO+H: 378,observed: 378.

N-Allyl, N-trifluoroacetyl-2-iodo-4-chlorophenethylamine

A solution of N-trifluoroacetyl-2-iodo-4-chlorophenethylamine (0.94 g,2.4 mmol) in toluene (25 mL) was treated with K₂CO₃ (0.43 g, 3.12 mmol),KOH (0.40 g, 7.2 mmol), n-Bu₄NBr (0.077 g, 0.24 mmol) and allyl bromide(0.43 g, 3.6 mmol) sequentially. The mixture was stirred at 80° C. for3.5 hours, cooled to 20° C. and acidified with 10% aqueous HCl. Thephases were separated, the aqueous phase extracted with ether (100 mL),the combined organic phases were washed with brine (50 mL), dried withNa₂SO₄ and concentrated to give 0.76 g of a clear oil. MS calculated forC₁₃H₁₂CIF₃INO+H: 418, observed: 418.

N-Trifluoroacetyl-8-chloro-1-methylene-2,3,4,5-tetrahydro-1H-3-benzazepine

A solution of N-allyl, N-trifluoroacetyl-2-iodo-4-chlorophenethylamine(0.76 g, 1.8 mmol) in dimethylformamide (20 mL) was treated with KOAc(0.53 g, 5.4 mmol), n-Bu₄NBr (0.58 g, 1.8 mmol), PPh₃ (0.047 g, 0.18mmol), Pd(OAc)₂ (0.041 g, 0.18 mmol) and stirred overnight at 105° C.The product mixture was cooled to 20° C., filtered, diluted with water(100 mL), extracted with ether (3×100 mL), the combined organic phaseswashed with water (100 mL), brine (100 mL), dried with Na₂SO₄ andconcentrated. Flash chromatography (10% EtOAc in hexane, silica)resulted in 0.228 g of a clear oil. ¹H NMR (400 MHz, CDCl₃) δ 7.29 (s,1H), 7.18 (m, 1H), 7.04 (m, 1H), 5.38 (m, 2H), 5.40 (d, J=16 Hz, 2H),3.80 (m, 2H), 3.00 (m, 2H). MS calculated for C₁₃H₁₁CIF₃NO+H: 290,observed: 290.

N-Trifluoroacetyl-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine

A solution ofN-trifluoroacetyl-8-chloro-1-methylene-2,3,4,5-trihydro-1H-3-benzazepine(0.16 g, 0.55 mmol) in methanol (10 mL) was treated with 10% Pd/C (0.02g) and stirred 30 minutes under an atmosphere of hydrogen. The productmixture was filtered, concentrated and purified by flash chromatography(5% EtOAc in hexane, silica) resulting in 0.057 g of a white solid. MScalculated for C₁₃H₁₃CIF₃NO+H: 292, observed: 292.

8-Chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine

A solution ofN-trifluoroacetyl-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine(65 mg, 0.22 mmol) in methanol (2 mL) was treated with 15% aqueous NaOH(2 mL), and stirred for 3.5 hours at 60° C. The product mixture wasconcentrated, extracted 3 times with CH₂Cl₂ (5 mL), dried with Na₂SO₄and concentrated to give 35 mg of a clear oil. ¹H NMR (400 MHz, CDCl₃) δ7.11 (s, 1H), 7.05 (d, J=8 Hz, 1H), 6.98 (d, J=8 Hz, 1H), 3.1-2.9 (m,6H), 2.71 (m, 1H), 2.68 (bs, 1H), 1.32 (d, J=8 Hz, 3H). MS calculatedfor C₁₁H₁₄CIN+H: 196, observed: 196.

An additional synthesis has been reported for the preparation of thetitle compound and the HCl salt in PCT publication WO2005/019179.

Example 27(R,S)7-(2-Methyl-2H-pyrazol-3-yl)-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine

N-Trifluoroacetyl-7-hydroxy-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine

A solution ofN-trifluoroacetyl-7-methoxy-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine(0.506 g, 1.76 mmol) in dichloromethane (20 mL) was treated with BBr₃(4.1 mL of a 1.0M solution in CH₂Cl₂, 4.1 mmol) and stirred overnightwhile warming to 20° C. The excess BBr₃ was quenched with water, and theresulting mixture was diluted with ether (200 mL), washed with Na₂CO₃(100 mL) and brine (100 mL), dried with Na₂SO₄ and concentrated. Flashchromatography (15% EtOAc in hexane, silica) resulted in 0.460 g of awhite solid foam. MS calculated for C₁₃H₁₄F₃NO₂+H: 274, observed: 274.

N-Trifluoroacetyl-7-hydroxy-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine,O-trifluoromethanesulfonate

A solution ofN-trifluoroacetyl-7-hydroxy-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine(460 mg, 1.76 mmol) in dichloromethane (15 mL) was treated with pyridine(417 mg, 5.27 mmol), trifluoromethanesulfonic anhydride (991 mg, 3.52mmol) and stirred 1.5 hours at 20° C. The product mixture was dilutedwith dichloromethane (100 mL), washed with water (50 mL), 5% aqueous HCl(50 mL), saturated aqueous NaHCO₃ (50 mL), brine (50 mL), dried withNa₂SO₄ and concentrated. Flash chromatography (15% EtOAc in hexane,silica) resulted in 658 mg of a clear oil. MS calculated forC₁₄H₁₃F₆NO₄S+H: 406, observed: 406.

N-Trifluoroacetyl-7-(2-Methyl-2H-pyrazol-3-yl)-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine

To a solution ofN-trifluoroacetyl-7-hydroxy-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine,O-trifluoromethanesulfonate (100 mg, 0.25 mmol) in dimethylformamide (2mL) was treated with (2-methyl-2H-pyrazol-3-yl)-tri-n-butyltin (138 mg,0.37 mmol), LiCl (21 mg, 0.50 mmol), Pd(PPh₃)₂Cl₂ (35 mg, 0.05 mmol) andstirred at 100° C. for 4 hours. The product mixture was diluted withEtOAc (20 mL), washed twice with water (10 mL), once with brine (10 mL),dried with Na₂SO₄ and concentrated. Flash chromatography (30% EtOAc inhexane, silica) resulted in 80 mg of a clear oil. MS calculated forC₁₇H₁₈F₃N₃O+H: 338, observed: 338.

7-(2-Methyl-2H-pyrazol-3-yl)-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine

A solution ofN-trifluoroacetyl-7-(2-Methyl-2H-pyrazol-3-yl)-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine(48 mg, 0.14 mmol) in methanol (2 mL) was treated with 15% aqueous NaOH(2 mL), and the solution stirred overnight at 20° C. The product mixturewas concentrated, extracted 3 times with CH₂Cl₂ (5 mL), dried withNa₂SO₄ and the solvent evaporated. Flash chromatography (0-15% MeOH inCH₂Cl₂, silica) resulted in 30 mg of a clear oil. ¹H NMR (400 MHz,CDCl₃) δ 7.48 (s, 1H), 7.21 (m, 2H), 7.13 (s, 1H), 6.27 (s, 1H), 3.89(s, 3H), 3.3-2.9 (m, 9H), 2.79 (dd, J=7, 14 Hz, 1H), 1.40 (d, J=8 Hz,3H). MS calculated for C₁₅H₁₉N₃+H: 242, observed: 242.

Example 28(R,S)7-(4-Bromo-2-methyl-2H-pyrazol-3-yl)-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine

N-Trifluoroacetyl-7-(4-bromo-2-Methyl-2H-pyrazol-3-yl)-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine

To a solution ofN-trifluoroacetyl-7-(2-Methyl-2H-pyrazol-3-yl)-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine(30 mg, 0.082 mmol) in dichloromethane (1 mL) was treated withN-bromosuccinimide (15.3 mg, 0.086 mmol) and stirred overnight at 20° C.The product mixture was absorbed on silica and purified by flashchromatography (2-5% MeOH in CH₂Cl₂, silica) resulting in 37 mg of awhite crystalline solid. MS calculated for C₁₇H₁₇BrF₃N₃O+H: 416,observed: 416.

7-(4-Bromo-2-methyl-2H-pyrazol-3-yl)-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine

A solution ofN-trifluoroacetyl-7-(4-bromo-2-Methyl-2H-pyrazol-3-yl)-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine(37 mg, 0.089 mmol) in methanol (2 mL) was treated with of 15% aqueousNaOH (2 mL), and stirred overnight at 20° C. The product mixture wasconcentrated, extracted 3 times with CH₂Cl₂ (5 mL), dried with Na₂SO₄and the solvent evaporated. Flash chromatography (0-15% MeOH in CH₂Cl₂,silica) resulted in 28 mg of a clear oil. ¹H NMR (400 MHz, CDCl₃) δ 7.50(s, 1H), 7.25 (d, J=8 Hz, 1H), 7.17 (d, J=8 Hz, 1H), 7.10 (s, 1H), 3.83(s, 3H), 3.17 (m, 1H), 3.1-2.9 (m, 8H), 2.80 (dd, J=7, 13 Hz, 1H), 2.48(bs, 1H), 1.40 (d, J=8 Hz, 3H). MS calculated for C₁₅H₁₈BrN₃+H: 320,observed: 320.

Example 29(R,S)7-(3-Chlorophenyl)-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine

A solution ofN-trifluoroacetyl-7-hydroxy-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine,O-trifluoromethanesulfonate (50 mg, 0.123 mmol) in 1,4-dioxane (1.5 mL)was treated with 2-chlorophenylboronic acid (39 mg, 0.243 mmol), CsF (56mg, 0.37 mmol), water (50 mg, 2.78 mmol), Pd(PPh₃)₄ (29 mg, 0.025 mmol)and stirred overnight at 75° C. The product mixture was diluted withEtOAc (20 mL), washed with water (10 mL), brine (10 mL), dried withNa₂SO₄ and concentrated. Flash chromatography (10-20% EtOAc in hexane,silica) resulted in 45 mg of a clear oil. MS calculated forC₁₉H₁₇CIF₃NO+H: 368, observed: 368. The product (27 mg, 0.073 mmol) wasdissolved in methanol (2 mL) treated with 15% aqueous NaOH (2 mL), andstirred overnight at 20° C. The product mixture was concentrated,extracted 3 times with CH₂Cl₂ (5 mL), dried with Na₂SO₄ and the solventevaporated to give 18 mg of a clear oil. ¹H NMR (400 MHz, CDCl₃) δ 7.54(s, 1H), 7.42 (d, J=6 Hz, 1H), 7.35-7.21 (m, 5H), 3.14 (m, 1H), 3.1-2.9(m, 8H), 2.80 (bm, 2H), 1.38 (d, J=8 Hz, 3H). MS calculated forC₁₇H₁₈ClN₃+H: 272, observed: 272.

Example 30(R,S)7-(2-Chlorophenyl)-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine

A solution ofN-trifluoroacetyl-7-hydroxy-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine,O-trifluoromethanesulfonate (50 mg, 0.123 mmol) in 1,4-dioxane (1.5 mL)was treated with 2-chlorophenylboronic acid (39 mg, 0.243 mmol), CsF (56mg, 0.37 mmol), water (50 mg, 2.78 mmol), Pd(PPh₃)₄ (29 mg, 0.025 mmol)and stirred overnight at 75° C. The product mixture was diluted withEtOAc (20 mL), washed with water (10 mL), brine (10 mL), dried withNa₂SO₄ and concentrated. Flash chromatography (10-20% EtOAc in hexane,silica) resulted in 36 mg of a clear oil. MS calculated forC₁₉H₁₇CIF₃NO+H: 368, observed: 368. The product (27 mg, 0.073 mmol) wasdissolved in methanol (2 mL) treated with 15% aqueous NaOH (2 mL), andstirred overnight at 20° C. The product mixture was concentrated,extracted 3 times with CH₂Cl₂ (5 mL), dried with Na₂SO₄ and the solventevaporated to give 24 mg of a clear oil. ¹H NMR (400 MHz, CDCl₃) δ 7.44(d, J=8 Hz, 1H), 7.35-7.22 (m, 5H), 7.15 (s, 1H), 3.14 (m, 1H), 3.1-2.9(m, 8H), 2.80 (dd, J=13, Hz, 1H), 2.51 (bs, 1H), 1.38 (d, J=8 Hz, 3H).MS calculated for C₁₇H₁₈ClN₃+H: 272, observed: 272.

Example 31 (R,S)8-Chloro-1-hydroxy-2,3,4,5-tetrahydro-1H-3-benzazepine

N-Trifluoroacetyl-8-chloro-1-oxo-, 3,4,4,5-trihydro-1H-3-benzazepine

A solution ofN-trifluoroacetyl-8-chloro-1-methylene-3,4,5-trihydro-1H-3-benzazepine(0.23 g, 0.80 mmol) in 1:1 methanol/dichloromethane (45 mL) was cooledto −78° C., treated with ozone until the solution turned blue (about 20minutes), PPh₃ (0.21 g, 0.80 mmol) was added and the resulting solutionwas stirred 90 minutes while warming to 20° C. The product mixture wasconcentrated and purified by flash chromatography (30% EtOAc in hexane,silica) resulting in 0.215 g of a white solid. MS calculated forC₁₂H₉CIF₃NO₂+H: 292, observed: 292.

8-Chloro-1-hydroxy-2,3,4,5-tetrahydro-1H-3-benzazepine

A solution ofN-trifluoroacetyl-8-chloro-1-oxo-3,4,5-trihydro-1H-3-benzazepine (50 mg,0.17 mmol) in methanol (2 mL) was treated with NaBH₄ and the resultingmixture was stirred 16 hours at 20° C. The white solid product wascollected by filtration, washed with water and dried, resulting in 30 mgof a white solid. ¹H NMR (400 MHz, CD₃OD) δ 7.39 (s, 1H), 7.12 (d, J=8Hz, 1H), 7.06 (d, J=8 Hz, 1H), 4.74 (d, J=8 Hz, 1H), 3.1-2.7 (m, 6H). MScalculated for C₁₀H₁₂ClNO+H: 198, observed: 198.

Example 32 (R,S)8-Bromo-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine

By the same general procedure as in example 26,(R,S)8-bromo-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine was obtainedfrom 4-bromophenethylamine as a colorless oil. ¹H NMR (400 MHz, CDCl₃) δ7.27 (s, 1H), 7.22 (d, J=8 Hz, 1H), 6.94 (d, J=8 Hz, 1H), 3.1-2.85 (m,6H), 2.72 (m, 1H), 2.25 (bs, 1H), 1.33 (d, J=7 Hz, 3H). MS calculatedfor C₁H₄BrN+H: 240, observed: 240.

Example 33 (R,S)8-Fluoro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine

By the same general procedure as in example 26,(R,S)8-fluoro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine was obtainedfrom 4-fluorophenethylamine as a colorless oil. ¹H NMR (400 MHz, CDCl₃)δ 7.00 (dd, J=8, 10 Hz, 1H), 6.86 (d, J=10 Hz, 1H), 6.76 (d, J=8 Hz,1H), 3.08-2.56 (m, 7H), 1.85 (bs, 1H), 1.31 (d, J=7 Hz, 3H). MScalculated for C₁₁H₁₄FN+H: 180, observed: 180.

Example 34 (R,S)7-Fluoro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine

By the same general procedure as in example 26,(R,S)7-fluoro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine was obtainedfrom 3-fluorophenethylamine as a colorless oil. ¹H NMR (400 MHz, CDCl₃)δ 7.09 (dd, J=6, 8 Hz, 1H), 6.85-6.78 (m, 2H), 3.10-2.89 (m, 6H), 2.71(dd, J=7, 13 Hz, 1H), 1.91 (bs, 1H), 1.33 (d, J=7 Hz, 3H). MS calculatedfor C₁₁H₁₄FN+H: 180, observed: 180.

Example 35 (R,S)7-Chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine

By the same general procedure as in example 26,(R,S)7-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine was obtainedfrom 3-chlorophenethylamine as a colorless oil. ¹H NMR (400 MHz, CDCl₃)δ 7.10 (d, J=8 Hz, 1H), 7.06 (m, 2H), 3.1-2.9 (m, 6H), 2.70 (dd, J=13, 7Hz, 1H), 1.89 (bs, 1H), 1.31 (d, J=7 Hz, 3H). MS calculated forCH₁₄CIN+H: 196, observed: 196.

Example 36 (R,S)7,8-Dichloro-1-m

By the same general procedure as in example 26,(R,S)7,8-dichloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine wasobtained from 3,4-dichlorophenethylamine as a colorless oil. ¹H NMR (400MHz, CDCl₃) δ 7.20 (s, 1H), 7.16 (s, 1H), 3.05-2.86 (m, 6H), 2.71 (dd,J=7, 13 Hz, 1H), 1.83 (bs, 1H), 1.33 (d, J=7 Hz, 3H). MS calculated forC₁₁H₁₃Cl₂N+H: 230, observed: 230.

Example 37(R,S)N-Methyl-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine

By the same general procedure as in example 9,(R,S)N-methyl-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine wasobtained from (R,S)8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepineas a colorless oil. MS calculated for C₁₂H₁₆CIN+H: 210, observed: 210.

Example 38(R,S)1-Methyl-7-trifluoromethoxy-2,3,4,5-tetrahydro-1H-3-benzazepine

By the same general procedure as in example 26,(R,S)1-methyl-7-trifluoromethoxy-2,3,4,5-tetrahydro-1H-3-benzazepine wasobtained from 3-trifluoromethoxyphenethylamine as a colorless oil. ¹HNMR (400 MHz, CD₃OD) δ 7.39 (d, J=8 Hz, 1H), 7.19 (m, 1H), 3.46 (m, 2H),3.38 (d, J=13 Hz, 1H), 3.29 (m, 1H), 3.16 (m, 2H), 3.05 (dd, J=13, 9 Hz,1H), 1.50 (d, J=8 Hz, 3H). MS calculated for C₁₂H₁₄F₃NO+H: 246,observed: 246.

Example 39(R,S)8-Iodo-1-methyl-7-trifluoromethoxy-2,3,4,5-tetrahydro-1H-3-benzazepine

By the same general procedure as in example 3,(R,S)8-iodo-1-methyl-7-trifluoromethoxy-2,3,4,5-tetrahydro-1H-3-benzazepinewas obtained fromN-trifluoroacetyl-1-methyl-7-trifluoromethoxy-2,3,4,5-tetrahydro-1H-3-benzazepineas a colorless oil. ¹H NMR (400 MHz, CD₃OD) δ 7.79 (s, 1H), 7.25 (s,1H), 3.46-3.40 (m, 3H), 3.28-3.12 (m, 3H), 3.07 (dd, J=13, 9 Hz, 1H),1.47 (d, J=7 Hz, 3H). MS calculated for C₁₂H₁₄F₃INO+H: 372, observed:372.

Example 40(R,S)N-Propyl-8-iodo-7-methoxy-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine

By the same general procedure as in example 10,(R,S)N-Propyl-8-iodo-7-methoxy-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepinewas obtained from(R,S)8-iodo-7-methoxy-1-methyl-1,2,4,5-tetrahydro-3H-3-benzazepine as acolorless oil. MS calculated for C₁₅H₂₂INO+H: 360, observed: 360.

Example 41(R,S)1-Ethyl-8-iodo-7-methoxy-2,3,4,5-tetrahydro-1H-3-benzazepine

By the same general procedure as in example 19,(R,S)1-ethyl-8-iodo-7-methoxy-2,3,4,5-tetrahydro-1H-3-benzazepine wasobtained fromN-trifluorolacetyl-1-ethyl-7-methoxy-2,3,4,5-tetrahydro-1H-3-benzazepineas a colorless oil. ¹H NMR (400 MHz, CDCl₃) δ 7.47 (s, 1H), 6.54 (s,1H), 3.86 (s, 3H), 3.20-2.97 (m, 4H), 2.93-2.75 (m, 3H), 2.64 (m, 1H),1.78 (m, 2H), 0.95 (dd, J=8, 8 Hz, 3H). MS calculated for C₁₃H₁₈NO+H:332, observed: 332.

Example 42(R,S)7-(3-Methoxyphenyl)-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine

By the same general procedure as in example 29,(R,S)7-(3-Methoxyphenyl)-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepinewas obtained fromN-trifluoroacetyl-7-hydroxy-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine,O-trifluoromethanesulfonate as a colorless oil. ¹H NMR (400 MHz, CDCl₃)δ 7.37 (dd, J=7, 7 Hz, 1H), 7.30 (m, 2H), 7.21 (d, J=7 Hz, 1H), 7.14 (d,J=7 Hz, 1H), 7.09 (s, 1H), 6.86 (d, J=8 Hz, 1H), 3.85 (s, 3H), 3.2-2.9(m, 6H), 2.80 (m, 1H), 2.64 (bs, 1H), 1.38 (d, J=7 Hz, 3H). MScalculated for C₁₈H₂₁NO+H: 268, observed: 268.

Example 43(R,S)7-(2,6-difluorophenyl)-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine

By the same general procedure as in example 29,(R,S)7-(2,6-difluorophenyl)-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepinewas obtained fromN-trifluoroacetyl-7-hydroxy-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine,O-trifluoromethanesulfonate as a colorless oil. ¹H NMR (400 MHz, CDCl₃)δ 7.35-7.10 (m, H), 6.95 (dd, J=7, 8 Hz, 1H), 3.2-2.9 (m, 6H), 2.79 (dd,J=8, 13 Hz, 1H), 2.70 (bs, 1H), 1.38 (d, J=8 Hz, 3H). MS calculated forC₁₇H₁₇F₂N+H: 274, observed: 274.

Example 44(R,S)7-(2-fluorophenyl)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine

By the same general procedure as in example 29,(R,S)7-(2-fluorophenyl)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepinewas obtained fromN-trifluoroacetyl-8-chloro-7-hydroxy-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepineas a colorless oil. ¹H NMR (400 MHz, CDCl₃) δ 7.35-7.23 (m, 3H),7.19-7.09 (m, 2H), 7.03 (s, 1H), 3.15-2.85 (m, 7H), 2.76 (dd, J=8, 13Hz, 1H), 1.36 (d, J=8 Hz, 3H). MS calculated for C₁₇H₁₇CIFN+H: 290,observed: 290.

Example 45(R,S)7-(2-Trifluoromethylphenyl)-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine

By the same general procedure as in example 29,(R,S)7-(2-trifluoromethylphenyl)-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepinewas obtained fromN-trifluoroacetyl-7-hydroxy-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine,O-trifluoromethanesulfonate as a colorless oil. ¹H NMR (400 MHz, CDCl₃)δ 7.71 (d, J=8 Hz, 1H), 7.52 (dd, J=7, 8 Hz, 1H), 7.42 (dd, J=7, 8 Hz,1H), 7.31 (d, J=7 Hz, 1H), 7.17 (d, J=8 Hz, 1H), 7.11 (d, J=8 Hz, 1H),3.15 (m, 1H), 3.1-2.9 (m, 5H), 2.76 (dd, J=8, 13 Hz, 1H), 2.37 (bs, 1H),1.38 (d, J=8 Hz, 3H). MS calculated for C₁₈H₁₈F₃N+H: 306, observed: 306.

Example 46(R,S)7-(3-Trifluoromethylphenyl)-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine

By the same general procedure as in example 29,(R,S)7-(3-trifluoromethylphenyl)-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepinewas obtained fromN-trifluoroacetyl-7-hydroxy-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine,O-trifluoromethanesulfonate as a colorless oil. ¹H NMR (400 MHz, CDCl₃)δ 7.80 (s, 1H), 7.73 (d, J=8 Hz, 1H), 7.57-7.48 (m, 2H), 7.38 (d, J=8Hz, 1H), 7.30 (s, 1H), 7.24 (d, J=7 Hz, 1H), 3.16 (m, 1H), 3.1-2.9 (m,6H), 2.79 (dd, J=8, 13 Hz, 1H), 1.38 (d, J=8 Hz, 3H). MS calculated forC₁₈H₁₈F₃N+H: 306, observed: 306.

Example 47(R,S)7-(4-Trifluoromethylphenyl)-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine

By the same general procedure as in example 29,(R,S)7-(4-trifluoromethylphenyl)-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepinewas obtained fromN-trifluoroacetyl-7-hydroxy-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine,O-trifluoromethanesulfonate as a colorless oil. ¹H NMR (400 MHz, CDCl₃)δ 7.65 (s, 4H), 7.38 (d, J=8 Hz, 1H), 7.31 (s, 1H), 7.24 (d, J=8 Hz,1H), 3.15 (m, 1H), 3.1-2.9 (m, 5H), 2.80 (dd, J=8, 13 Hz, 1H), 2.48 (bs,1H), 1.38 (d, J=8 Hz, 3H). MS calculated for C₁₈H₁₈F₃N+H: 306, observed:306.

Example 48(R,S)8-(2-Chlorophenyl)-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine

A solution ofN-trifluoroacetyl-8-bromo-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine(84 mg, 0.229 mmol) in dimethylformamide (2.5 mL) was treated with2-chlorophenylboronic acid (43 mg, 0.275 mmol), CsF (52 mg, 0.34 mmol),water (70 mg, 3.9 mmol), Pd(PPh₃)₄ (27 mg, 0.023 mmol) and stirredovernight at 75° C. The product mixture was diluted with EtOAc (20 mL),washed with water (10 mL), brine (10 mL), dried with Na₂SO₄ andconcentrated. Flash chromatography (10-20% EtOAc in hexane, silica)resulted in 36 mg of a clear oil. MS calculated for C₁₉H₁₇CIF₃NO+H: 368,observed: 368. The product (39 mg, 0.106 mmol) was dissolved in methanol(2 mL) treated with 15% aqueous NaOH (2 mL), and stirred overnight at20° C. The product mixture was concentrated, extracted 3 times withCH₂Cl₂ (5 mL), dried with Na₂SO₄ and the solvent evaporated to give 18mg of a clear oil. ¹H NMR (400 MHz, CDCl₃) δ 7.44 (d, J=8 Hz, 1H),7.35-7.17 (m, 5H), 7.12 (d, J=8 Hz, 1H), 3.14 (m, 1H), 3.1-2.9 (m, 5H),2.79 (dd, J=7.13 Hz, 1H), 2.36 (bs, 1H), 1.36 (d, J=7 Hz, 3H). MScalculated for C₁₇H₁₈ClN₃+H: 272, observed: 272.

Example 49(R,S)7-Methoxy-1-methyl-8-trifluoromethyl-2,3,4,5-tetrahydro-1H-3-benzazepine

A solution ofN-trifluoromethylacetyl-8-iodo-7-methoxy-1-methyl-1,2,4,5-tetrahydro-3H-3-benzazepine(135 mg, 0.327 mmol) in dimethylformamide (3 mL) and toluene (0.5 mL)was treated with sodium trifluoroacetate (133 mg, 0.981 mmol), copper(I) iodide (124 mg, 0.654 mmol) and the toluene distilled off to removeany residual water. The reaction mixture was stirred at 155° C. for 3.5hours, diluted with EtOAc, filtered, absorbed on silica and purified byflash chromatography (10% EtOAc in hexane, silica) resulting in 26 mg ofa colorless oil. MS calculated for C₁₅H₁₅F₆NO₂+H: 356, observed: 356.The intermediate (26 mg, 0.073 mmol) in methanol (2 mL) was treated with15% aqueous NaOH (2 mL), and stirred 0.5 hours at 50° C. The productmixture was diluted with water (5 mL), extracted twice with EtOAc (5mL), the combined organic phases were washed with brine (5 mL), driedwith Na₂SO₄ and concentrated to give 14 mg of a colorless oil. ¹H NMR(400 MHz, CDCl₃) δ 732 (s, 1H), 6.73 (s, 1H), 3.89 (s, 3H), 3.1-2.9 (bm,6H), 2.75 (bm, 1H), 2.23 (bs, 1H), 1.36 (d, J=8 Hz, 3H). MS calculatedfor C₁₃H₁₆F₃NO*H: 260, observed: 260.

Example 50(R,S)7-Methoxy-1-methyl-8-pentafluoroethyl-2,3,4,5-tetrahydro-1H-3-benzazepine

A solution ofN-trifluoromethylacetyl-8-iodo-7-methoxy-1-methyl-1,2,4,5-tetrahydro-3H-3-benzazepine(100 mg, 0.242 mmol) in dimethylformamide (3 mL) and toluene (1 mL) wastreated with sodium pentafluoropropionate (64 mg, 0.344 mmol), copper(I) iodide (92 mg, 0.484 mmol) and the toluene distilled off to removeany residual water. The reaction mixture was stirred at 160° C. for 3.5hours, diluted with EtOAc, filtered, absorbed on silica and purified byflash chromatography (10% EtOAc in hexane, silica) resulting in 22 mg ofa colorless oil. MS calculated for C₁₆H₁₅F₈NO₂+H: 406, observed: 406.The intermediate (22 mg, 0.054 mmol) in methanol (2 mL) was treated with15% aqueous NaOH (2 mL), and stirred 0.5 hours at 50° C. The productmixture was diluted with water (5 mL), extracted twice with EtOAc (5mL), the combined organic phases were washed with brine (5 mL), driedwith Na₂SO₄ and concentrated to give 14 mg of a colorless oil. ¹H NMR(400 MHz, CDCl₃) δ 7.25 (s, 1H), 6.74 (s, 1H), 3.85 (s, 3H), 3.1-2.9(bm, 6H), 2.76 (bm, 1H), 2.37 (bs, 1H), 1.35 (d, J=8 Hz, 3H). MScalculated for C₁₄H₁₆F₅NO+H: 310, observed: 310.

Example 51(R,S)8-Trifluoromethyl-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine

By the same general procedure as in example 26,(R,S)8-trifluoromethyl-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine wasobtained from 4-trifluoromethylphenethylamine as a colorless oil. ¹H NMR(400 MHz, DMSO) 7.55 (d, J=8 Hz, 1H), 7.49 (s, 1H), 7.43 (d, J=8 Hz,1H), 3.55-3.50 (m, 1H) 3.43-3.23 (m, 7H), 3.13 (dd, J=16, 7 Hz, 1H),3.0-2.91 (m, 2H), 1.36 (d, J=7 Hz, 3H). MS calculated for C₁₂H₁₄F₃N+H,230.19, observed: 230.4

Example 52(R,S)8-bromo-1-methoxymethyl-7-methoxy-2,3,4,5-tetrahydro-1H-3-benzazepine

A solution of8-bromo-1-hydroxymethyl-7-methoxy-2,3,4,5-tetrahydro-1H-3-benzazepine(0.075 g, 0.26 mmol) in dichloromethane (2 mL) was treated with BOC₂O(0.062 g, 0.29 mmol), and stirred overnight at 20° C. The product wasabsorbed on silica and purified by flash chromatography (33% EtOAc inhexane, silica) resulting in 0.034 g of a clear oil. MS calculated forC₁₇H₂₄BrNO₄+H: 386, observed: 386. The BOC-protected intermediate wasdissolved in dimethylformamide (1 mL), treated with excess NAH andexcess iodomethane sequentially, and then stirred for 1 hour at 20° C.The reaction mixture was quenched with water (5 mL), extracted twicewith EtOAc (5 mL), the combined organic phases were washed with brine (5mL), dried with Na₂SO₄ and concentrated to give 0.019 g of a clear oil.MS calculated for C₁₈H₂₆BrNO₄+H: 400, observed: 400. The N—BOC protectedmethylether was then treated with 4M HCl in dioxane (1 mL) and stirred 2hours at 20° C. Evaporation resulted in 0.009 g of the desired productas a clear oil. ¹H NMR (400 MHz, CD₃OD) δ 7.30 (s, 1H), 6.92 (s, 1H),3.87 (s, 3H), 3.65 (s, 3H) 3.5-3.1 (m, 9H). MS calculated forC₁₃H₁₈BrNO₂+H: 300, observed: 300.

Example 53 (R,S)8-Chloro-1-ethyl-2,3,4,5-tetrahydro-1H-3-benzazepine

N-Crotyl, N-trifluoroacetyl-2-iodo-4-chlorophenethylamine

A solution of N-trifluoroacetyl-2-iodo-4-chlorophenethylamine (6.2 g,15.8 mmol) in dimethylformamide (350 mL) was treated with K₂CO₃ (15.8 g,114 mmol) and crotyl bromide (6.0 g, 44 mmol) sequentially, the mixturewas stirred at 60° C. for 16 hours and then cooled to 20° C. The mixturewas diluted with EtOAc (350 mL), washed with water (3×300 mL), driedwith Na₂SO₄ and concentrated. Flash chromatography (5-15% EtOAc inhexane) resulted in 2.5 g of a clear oil. MS calculated forC₁₄H₁₄CIF₃INO+H: 432, observed: 432.

N-Trifluoroacetyl-8-chloro-1-ethyl-2,3,4,5-tetrahydro-1H-3-benzazepine

A solution of N-crotyl, N-trifluoroacetyl-2-iodo-4-chlorophenethylamine(2.5 g, 5.8 mmol) in dimethylformamide (250 mL) was treated with KOAc(1.07 g, 10.9 mmol), n-Bn₂Et₂NBr (1.33 g, 5.84 mmol), Pd(OAc)₂ (0.063 g,0.28 mmol) and stirred overnight at 77° C. The product mixture wascooled to 20° C., filtered, diluted with water (100 mL), extracted withEtOAc (3×100 mL), the combined organic phases washed with water (100mL), brine (100 mL), dried with Na₂SO₄ and concentrated. Flashchromatography (2-20% EtOAc in hexane, silica) resulted in 0.339 g of aclear oil. The product, which was assumed to be a mixture of double-bondisomers, was dissolved in methanol (50 mL) treated with Et₃N (0.2 mL),10% Pd/C (0.10 g) and stirred 16 hours under 100 psi of hydrogen. Theproduct mixture was filtered, concentrated and purified by flashchromatography (5% EtOAc in hexane, silica) resulting in 0.20 g of awhite solid. MS calculated for C₁₄H₁₅CIF₃NO+H: 306, observed: 306.

8-Chloro-1-ethyl-2,3,4,5-tetrahydro-1H-3-benzazepine

A solution ofN-trifluoroacetyl-8-chloro-1-ethyl-2,3,4,5-tetrahydro-1H-3-benzazepine(63 mg, 0.207 mmol) in methanol (2 mL) was treated with 15% aqueous NaOH(2 mL), and stirred for 3.5 hours at 60° C. The product mixture wasconcentrated, extracted 3 times with CH₂Cl₂ (5 mL), dried with Na₂SO₄and concentrated to give 35 mg of a clear oil. ¹H NMR (400 MHz, DMSO-d₆)δ 7.2 (m, 3H), 3.3-3.0 (m, 7H), 1.9-1.6 (m, 2H), 0.91 (t, J=7 Hz, 3H).MS calculated for C₁₂H₁₆CIN+H: 210, observed: 210.

Example 54(R,S)8-Chloro-7-fluoro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine

N-Trifluoroacetyl-8-chloro-7-fluoro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine

A solution ofN-trifluoroacetyl-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine(2.5 g, 8.5 mmol) in 1,2-dichloroethane (15 mL) was treated withSelectfluor (3.9 g, 11 mmol), trifluoromethanesulfonic acid (8 mL, 90mmol) and stirred 60 hours at 75° C. The product mixture was poured intowater (200 mL), extracted with EtOAc (200 mL), the organic phase washedwith saturated aqueous NaHCO₃ (2×100 mL), brine (100 mL), dried withNa₂SO₄ and concentrated. The crude product was purified by flashchromatography (6% EtOAc in hexane, silica) resulting in 1.6 g of awhite solid. MS calculated for C₁₃H₁₂CIF₄NO+H: 310, observed: 310.

8-Chloro-7-fluoro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine

A solution ofN-trifluoroacetyl-8-chloro-7-fluoro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine(160 mg, 0.22 mmol) in methanol (3 mL) was treated with 15% aqueous NaOH(2 mL), and stirred for 3.5 hours at 25° C. The product mixture wasconcentrated, extracted 3 times with CH₂Cl₂ (5 mL), dried with Na₂SO₄and concentrated to give 93 mg of a clear oil. ¹H NMR (400 MHz, CDCl₃) δ7.11 (m, 1H), 6.85 (m, 1H), 3.05-2.95 (m, 3H), 2.95-2.80 (m, 3H), 2.68(m, 1H), 2.38 (bm, 1H), 1.31 (m, 3H). MS calculated for C₁₁H₁₃CIFN+H:214, observed: 214.

Example 55 Separation of Enantiomers for Selected Compounds of theInvention

The following compounds were separated into their respective enantiomersusing a Varian ProStar HPLC system with a 20 mm×250 mm Chiralcel ODchiral column, eluting with 0.2% diethylamine in various concentrationsof isopropanol (IPA) in hexanes, see Table 2 below. In some cases, theseparations were performed on the intermediate trifluoroacetamideprotected amines.

TABLE 2 Retention time Retention time Exam- Enan- for the free for thetrifluoro- ple tiomer amine (mins) acetamide Conditions 1 1 21.9 5% IPAin hexane 2 24.5 10 mL/min  2 1 42 5% IPA in hexane 2 47 9 mL/min 3 120.8 5% IPA in hexane 2 24.2 10 mL/min  19 1 34.9 1% IPA in hexane 239.5 9 mL/min 26 1 23.8 ¹ 5% IPA in hexane 2 29.2 ² 7 mL/min 37 1 23.8 ³5% IPA in hexane 2 29.2 ⁴ 7 mL/min 51 1 18.6 ⁵ 1% IPA in hexane 2 21.4 ⁶9 mL/min 53 1 13.7 ⁷ 5% IPA in hexane 2 20.2 ⁸ 10 mL/min  ¹ Theseparated trifluoroacetamide enantiomer was hydrolyzed to giveEnantiomer 1 of Compound 26. ² The separated trifluoroacetamideenantiomer was hydrolyzed to give Enantiomer 2 of Compound 26. ³ Theseparated trifluoroacetamide enantiomer was hydrolyzed and subsequentlyN-methylated to give Enantiomer 1 of Compound 37. ⁴ The separatedtrifluoroacetamide enantiomer was hydrolyzed and subsequentlyN-methylated to give Enantiomer 2 of Compound 37. ⁵ The separatedtrifluoroacetamide enantiomer was hydrolyzed to give Enantiomer 1 ofCompound 51. ⁶ The separated trifluoroacetamide enantiomer washydrolyzed to give Enantiomer 2 of Compound 51. ⁷ The separatedtrifluoroacetamide enantiomer was hydrolyzed to give Enantiomer 1 ofCompound 53. ⁸ The separated trifluoroacetamide enantiomer washydrolyzed to give Enantiomer 2 of Compound 53.

Example 56 Intracellular IP₃ Accumulation Assay

HEK293 cells were transfected in 15 cm sterile dishes with or without(control) 16 μg of human 5-HT_(2C) receptor cDNA using 25 μl oflipofectamine. Cells were then incubated for 3-4 hours at 37° C./5% CO₂and then transfection media was removed and replaced with 100 μl ofDMEM. Cells were then plated onto 100 cm sterile dishes. The next daycells were plated into 96 well PDL microtiter plates at a density of55K/0.2 ml. Six hours latter, media was exchanged with [³H]inositol(0.25 μCi/well) in inositol free DMEM and plates were incubated at 37°C./5% CO₂ overnight. The next day, wells were aspirated and 200 μl ofDMEM containing test compound, 10 μM pargyline, and 10 mM LiCl was addedto appropriate wells. Plates were then incubated at 37° C./5% CO₂ forthree hours followed aspiration and by addition of fresh ice cold stopsolution (1M KOH, 19 mM Na-borate, 3.8 mM EDTA) to each well. Plateswere kept on ice for 5-10 min and the wells were neutralized by additionof 200 μl of fresh ice cold neutralization solution (7.5% HCl). Plateswere then frozen until further processing is desired. The lysate wasthen transferred into 1.5 ml Eppendorf tubes and 1 ml ofchloroform/methanol (1:2) was added/tube. The solution was vortexed for15 seconds and the upper phase was applied to a Biorad AG1-X8™ anionexchange resin (100-200 mesh). First, the resin was washed with water at1:1.25 W/V and 0.9 ml of upper phase was loaded onto the column. Thecolumn was then washed with 10 ml of 5 mM myo-inositol and 10 ml of 5 mMNa-borate/60 mM Na-formate. The inositol tris phosphates were elutedinto scintillation vials containing 10 ml of scintillation cocktail with2 ml of 0.1 M formic acid/1M ammonium formate. The columns wereregenerated by washing with 10 ml of 0.1M formic acid/3M ammoniumformate and rinsed twice with dd H₂O and stored at 4° C. In water.

The biological activities in the IP Accumulation Assay for severalrepresentative compounds are shown in Table 3 below:

TABLE 3 Compound 5-HT_(2C) (EC₅₀)* (Example Number) IP AccumulationAssay (nM) 1 4.2 2 4.5 3 1.4 4 2.1 5 12.1 12 6.3 19 18 26 5.8 32 2.1*Reported values are averages of at least two trials.

The majority of the other compounds of the Examples were tested at leastonce, and they showed activities in the IP Accumulation Assay in therange between ˜1.4 nM and ˜5 μM.

Example 57 Inhibition of Food Intake in Food-Deprived Rats

Male Sprague-Dawley rats (250-350 g) were deprived of food overnightprior to testing. Prior to food deprivation, the animals were weighedand separated into treatment groups in order to balance groups accordingto body weight. On the test day, animals were placed into individualcages (no bedding) at 9:00 am with free access to water. At 10:00 am,animals were injected with test compound (p.o., i.p., or s.c.) and thenpresented with a pre-weighed amount of food in a dish either 60 min(p.o.) or 30 min (i.p. and s.c.) after drug administration. Foodconsumption over different time points was then determined by weighingthe food cup at 1, 2, 4, and 6 hr after the food was presented. Thus,food consumption was measured at 2, 3, 5, and 7 hr post-injection inp.o. studies, and at 1.5, 2.5, 4.5, and 6.5 hr post-injection in i.p.and s.c. studies.

FIGS. 1A-G illustrate the effects of seven different compounds on foodintake in food-deprived rats. All compounds inhibited food intakedose-dependently. This effect was consistently most pronounced over thefirst 1 hr after food presentation. Some compounds (FIGS. 1A, 1C, and1E) maintained an inhibitory effect on food intake relative tovehicle-treated controls at 6 hr after food presentation. Compounds werealso shown to be effective via all routes of administration includingp.o.

Example 58 Inhibition of Food Intake in Food-Deprived Rats Using aSelective 5HT-2C Receptor Agonist Alone, Phentermine Alone, or aCombination of the Two Compounds

Male SD rats, weight 250-275 g, were purchased from Harlan and housed 4per cage in an animal facility in reverse day-light. Water and Chow wasavailable (LabDiet 8604) ad libitum for two weeks. The animals werehandled for 2 occasions during this time. On the morning of the study,the animals were single-housed with no food or bedding and dosedperorally with 1 ml/kg of compound or vehicle 30 minutes prior to lightsout. At lights out, the animals were given a pre-weighed amount of chowand placed near the food bowl. Two hours later the remaining chow wasweighed and the study concluded.

FIG. 2 shows the effect on feeding of the selective 5HT-2C receptoragonist 8-Chloro-7-methoxy-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine(Cmpd A), phentermine, and the combination. A synthesis example for8-Chloro-7-methoxy-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine (Cmpd A)can be found in Example 2 herein.

Example 59 Inhibition of Food Intake in Food-Deprived Rats Using aSelective 5HT-2C Receptor Agonist Alone, Phentermine Alone, or aCombination of the Two Compounds

Female (weight 225-250 g) and male (weight 250-275 g) Sprague-Dawley(SD) rats were purchased from Harlan (San Diego, Calif.) and housed 4per cage in a temperature controlled environment under a 17 h/7 hlight/dark cycle (lights out at 10:00 am). Water and Chow was available(LabDiet 8604) ad libitum for two weeks. The animals were handled for 2occasions during this time. On the morning of the study, the animalswere individually housed with no food or bedding and dosed perorallywith 1 ml/kg of compound or vehicle 30 minutes prior to lights out. Atlights out, the animals were given a pre-weighed amount of chow andplaced near the food bowl. Two hours later the remaining chow wasweighed and the study concluded.

FIG. 3 shows the effect of the selective 5HT-2C receptor agonist(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine (Compound B),phentermine, and the combination on food intake. A synthesis example for(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine (Compound B)can be found in Example 26 herein.

The effect of Compound B, phentermine, and the combination on foodintake in female rats is shown in FIG. 3A. For analysis, the data wassubjected to a two-way analysis of variance (ANOVA) with phentermine andCompound B as independent factors. The analysis revealed a significantinteraction between the two factors [F(1,29)=31.6, p<0.01]. Posthocpairways comparisons using the Bonferroni multiple comparison testrevealed the Compound B+phentermine combination to differ significantlyfrom all other groups (p<0.01, see FIG. 3A), evidencing a supra additive(synergistic) effect for the inhibition of food intake. No othersignificant differences between groups were observed.

The effect of Compound B, phentermine, and the combination on foodintake in male rats is shown in FIG. 3B. For analysis, the data wassubjected to a two-way analysis of variance (ANOVA) with phentermine andCompound B as independent factors. The analysis revealed a significantinteraction between the two factors [F(1,29)=12.7, p<0.01]. Posthocpairways comparisons using the Bonferroni multiple comparison testrevealed the Compound B+phentermine combination to differ significantlyfrom all other groups (p<0.01, see FIG. 3B), evidencing a supra additive(synergistic) effect for the inhibition of food intake. No othersignificant differences between groups were observed.

Example 60 Inhibition of Food Intake in Food-Deprived Rats Using aSelective 5HT-2C Receptor Agonist Alone, Phentermine Alone, or aCombination of the Two Compounds

Male and female Sprague-Dawley (SD) rats (weight 250-275 g) werepurchased from Harlan (San Diego, Calif.) and housed 4 per cage in atemperature controlled environment under a 17 h/7 h light/dark cycle(lights out at 10:00 am). Water and Chow was available (LabDiet 8604) adlibitum for two weeks. The animals were handled for 2 occasions duringthis time. On the morning of the study, the animals were individuallyhoused with no food or bedding and dosed perorally with 1 ml/kg ofcompound or vehicle 30 minutes prior to lights out. At lights out, theanimals were given a pre-weighed amount of chow and placed near the foodbowl. Two hours later the remaining chow was weighed and the studyconcluded.

FIGS. 4A and 4B show the supra additive (synergistic) effect ofphentermine and the selective 5HT-2C receptor agonist(R)-1-(5-Chloro-2-fluoro-phenyl)-2-methyl-piperazine (Cmpd C) on foodintake in female (FIG. 4A) and male (FIG. 4B) rats.

Compound C is a selective 5HT-2C receptor agonist which lies outside ofFormula I as disclosed herein. Compound C was prepared in a similarmanner as described in PCT publication WO 2005/016902 (see Example 3.2therein) using 2-bromo-4-chloro-1-fluorobenzene as the startingmaterial.

It is intended that each of the patents, applications, printedpublications, and other published documents mentioned or referred to inthis specification be herein incorporated by reference in theirentirety.

Those skilled in the art will appreciate that numerous changes andmodifications can be made to the preferred embodiments of the inventionand that such changes and modifications can be made without departingfrom the spirit of the invention. It is therefore intended that theappended claims cover all such equivalent variations as fall within thetrue spirit and scope of the invention.

1.-41. (canceled)
 42. A method of decreasing food intake in a mammalcomprising the step of: administering to said mammal1,1-dimethyl-2-phenyl-ethylamine, or a pharmaceutically acceptable saltthereof, and (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepineor a pharmaceutically acceptable salt thereof.
 43. The method of claim42, wherein each of the 1,1-dimethyl-2-phenyl-ethylamine, or apharmaceutically acceptable salt thereof, and the(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt thereof is formulated for oraladministration.
 44. The method of claim 42, wherein each of the1,1-dimethyl-2-phenyl-ethylamine, or a pharmaceutically acceptable saltthereof, and the(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt thereof is formulated as a solid dosageform.
 45. The method of claim 42, wherein each of the1,1-dimethyl-2-phenyl-ethylamine, or a pharmaceutically acceptable saltthereof, and the(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt thereof is formulated as a liquiddosage form.
 46. The method of claim 42, wherein the1,1-dimethyl-2-phenyl-ethylamine, or a pharmaceutically acceptable saltthereof, and the(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt thereof are present in a combinedpreparation for simultaneous, separate or sequential use.
 47. A methodof decreasing food intake in a mammal comprising the step of:administering to said mammal 1,1-dimethyl-2-phenyl-ethylamine, or apharmaceutically acceptable salt thereof, and a hydrochloric acid saltof (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine.
 48. Themethod of claim 47, wherein each of the1,1-dimethyl-2-phenyl-ethylamine, or a pharmaceutically acceptable saltthereof, and the hydrochloric acid salt of(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine is formulatedfor oral administration.
 49. The method of claim 47, wherein each of the1,1-dimethyl-2-phenyl-ethylamine, or a pharmaceutically acceptable saltthereof, and the hydrochloric acid salt of(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine is formulatedas a solid dosage form.
 50. The method of claim 47, wherein each of the1,1-dimethyl-2-phenyl-ethylamine, or a pharmaceutically acceptable saltthereof, and the hydrochloric acid salt of(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine is formulatedas a liquid dosage form.
 51. The method of claim 47, wherein the1,1-dimethyl-2-phenyl-ethylamine, or a pharmaceutically acceptable saltthereof, and the hydrochloric acid salt of(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine are present ina combined preparation for simultaneous, separate or sequential use. 52.A method for preparing a composition comprising1,1-dimethyl-2-phenyl-ethylamine, or a pharmaceutically acceptable saltthereof, and (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepineor a pharmaceutically acceptable salt thereof, said method comprisingcombining 1,1-dimethyl-2-phenyl-ethylamine, or a pharmaceuticallyacceptable salt thereof, and(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt thereof.
 53. A method for preparing acomposition comprising 1,1-dimethyl-2-phenyl-ethylamine, or apharmaceutically acceptable salt thereof, and(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt thereof, said method comprisingcombining 1,1-dimethyl-2-phenyl-ethylamine, or a pharmaceuticallyacceptable salt thereof,(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt thereof, and one or morepharmaceutically acceptable carriers.
 54. A method for preparing acomposition comprising 1,1-dimethyl-2-phenyl-ethylamine, or apharmaceutically acceptable salt thereof, and(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt thereof, said method comprisingcombining 1,1-dimethyl-2-phenyl-ethylamine, or a pharmaceuticallyacceptable salt thereof, and(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt thereof to form a tablet or capsule.55. A method of preparing a composition comprising1,1-dimethyl-2-phenyl-ethylamine, or a pharmaceutically acceptable saltthereof, and (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepineor a pharmaceutically acceptable salt thereof, said method comprisinguniformly mixing 1,1-dimethyl-2-phenyl-ethylamine, or a pharmaceuticallyacceptable salt thereof, and(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt thereof with one or more liquidexcipients and/or solid excipients.
 56. A method of preparing acomposition comprising 1,1-dimethyl-2-phenyl-ethylamine, or apharmaceutically acceptable salt thereof, and(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt thereof, comprising uniformly mixingcompound 1,1-dimethyl-2-phenyl-ethylamine, or a pharmaceuticallyacceptable salt thereof, and(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt thereof with a liquid or a finelydivided solid carrier, or both.